MXPA05000979A - Substituted glycine derivatives for use as medicaments. - Google Patents

Substituted glycine derivatives for use as medicaments.

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Publication number
MXPA05000979A
MXPA05000979A MXPA05000979A MXPA05000979A MXPA05000979A MX PA05000979 A MXPA05000979 A MX PA05000979A MX PA05000979 A MXPA05000979 A MX PA05000979A MX PA05000979 A MXPA05000979 A MX PA05000979A MX PA05000979 A MXPA05000979 A MX PA05000979A
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Mexico
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alkyl
formula
compound
amino
pain
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MXPA05000979A
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Spanish (es)
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Wai-Lam Alexis Chu
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Pfizer
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    • C07C323/23—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
    • C07C323/24—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/25—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
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    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
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    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C229/06—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton
    • C07C229/10—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings
    • C07C229/12—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings to carbon atoms of acyclic carbon skeletons
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    • C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C229/06—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton
    • C07C229/10—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings
    • C07C229/14—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings to carbon atoms of carbon skeletons containing rings
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    • C07C323/23—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
    • C07C323/31—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton
    • C07C323/32—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton having at least one of the nitrogen atoms bound to an acyclic carbon atom of the carbon skeleton
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    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines

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Abstract

The compounds of formula (I) are substituted glycine derivatives useful in the treatment of epilepsy, faintness attacks, hypokinesia, cranial disorders, neurodegenerative disorders, depression, anxiety, panic, pain, arthritis, neuropathological disorders, sleep disorders, visceral pain disorders and gastrointestinal disorders. Processes for the preparation of the final products and intermediates useful in the process are included. Pharmaceutical compositions containing one or more of the compounds are also included. Formula (I) wherein R' is hydroxycarbonyl, a carboxylic acid biostere or prodrug thereof; R3, R3a, R2 and R2a are independently selected from H, C1-C6 alkyl, and Cl-C6 alkoxy Cl-C6 alkyl.

Description

GLYCINE DERIVATIVES SUBSTITUTED FOR USE AS MEDICINES The invention relates to substituted glycine derivatives useful as pharmaceutical agents, to processes for their production, to compositions containing them and to their use for the treatment of the conditions described below. BACKGROUND OF THE INVENTION Gabapentin (Neurontin®) is an anti-convulsant agent useful in the treatment of epilepsy and has recently been shown to be a potential treatment for neurogenic pain. It is l- (aminomethyl) -cyclohexylacetic acid of the structural formula: Gabapentin is one of the series of compounds of the formula wherein R is hydrogen or a lower alkyl radical and n is 4, 5 or 6. These compounds are described in the international publication US-A-4024175 and its US-A- 4087544 divisional. Its described uses are: protection against spasm Induced by thiosemicarbazide; protection against cardiac spasm; brain diseases, epilepsy, syncopes, hypokinesia and cranial traumas; and improvement in brain functions. The compounds are useful in geriatric patients. The descriptions of the two previously mentioned patents are incorporated herein by reference.
II International publication WO 0230871 describes compounds of type I and international publication WO 0222568 describes compounds of type II. The compounds also have affinity towards the binding site of gabapentin and preferably have physiological activities similar to gabapentin, particularly with respect to analgesia. Some compounds of the main structural types within the claims are exemplified in other publications, however, their use is not related to that of the current description. Examples include N- (2-phenoxy-ethyl) -alanine (Beilstein reg: 5407903, J. Med. Chem., 1974, 337-8), N- (2-benzylsulfanyl-ethyl) -glycine (Beilstein reg. , J. Am. Chem. Soc, 1948, 1620) and N- (2-phenylsulfanyl-ethyl) -glycine (Beilstein reg. 6707704, J. Med. Chem., 1975, 50-53). SUMMARY OF THE INVENTION The present invention provides substituted glycine derivatives and their prodrugs, pharmaceutically acceptable salts and solvates useful in the treatment of a variety of disorders, including epilepsy, syncope, hypokinesia, cranial disorders, neurodegenerative disorders, depression, anxiety, panic, pain, sleep disorders, osteoarthritis, rheumatoid arthritis and neuropathological disorders. The compounds provided may also be useful in the treatment of visceral pain, functional bowel disorders, such as gastroesophageal reflux, dyspepsia, irritable bowel syndrome and functional abdominal pain syndrome, and inflammatory bowel diseases such as Crohn's disease, ileitis and ulcerative colitis and Other types of visceral pain associated with dysmenorrhea, pelvic pain, cystitis and pancreatitis. They can also be used for the treatment of premenstrual syndrome. Therefore, the present invention provides the use of a compound of the formula (I) or a pharmaceutically acceptable salt or solvate thereof, as a medicament; Formula (I) wherein R 1 is hydroxycarbonyl, a biosterol carboxylic acid or one of its prodrugs; R3, R3a, Rz and R2a are independently selected from H, C1-C6 alkyl and Ci-Ce alkoxy C-i-Ce alkyl, Z is either; (i) a 5-membered heterocycloalkyl or heteroaryl bonded to C substituted with C6 alkyl or fused with C3-C8 cycloalkyl, monocyclic heteroaryl, phenyl or 4-8 membered heterocycloalkyl, wherein the fused ring is optionally substituted with one or two substituents selected from the group consisting of halogen, Ci-C6 alkyl, alkoxy CrC6, C1-C6 perfluoroalkyl, Ci-C6 perfluoroalkoxy, Ci-C6 amino cyanoalkyl, C6 alkylthio, C3-C8 cycloalkyl, monocyclic heteroaryl, phenyl and 4-8 membered heterocycloalkyl; or (ii) the group; wherein R 4 and R 4a are independently H, CrC 6 alkyl, C 1 -C 6 alkoxy or C 1 -C 6 alkoxy C 1 -C 6 alkyl; R5 is Ci-C6 alkyl, C3-C12 cycloalkyl, 4-12 membered heterocycloalkyl, aryl or heteroaryl and R5 is optionally substituted with one or two substituents selected from the group consisting of halogen, Ci-C6 alkyl, C1-C6 alkoxy , C1-C6 perfluoroalkyl, C1-C6 perfluoroalkoxy, cyano, C1-C6 amino alkyl, d-C6 amino dialkyl, CrC6 aminoalkyl, Ci-C6 alkyl Ci-C6 aminoalkyl, C6 dialkyl aminoalkyl Cf-Ce, Ci-C6 alkyl thio , C3-Ce cycloalkyl, monocyclic heteroaryl, phenyl and 4-8 membered heterocycloalkyl; I am good; (i) Y is S, O, NH or CH2 and X is a direct bond or C1-C2 alkyl, optionally substituted with Ci-Ce alkyl, Ci-Ce dialkyl or 1-4 fluorine atoms; or (ii) X is S, O, CH2 or NH and Y is C1-C2 alkyl, optionally substituted with Ci-C6 alkyl or dialkyl CrC6 or 1-4 fluorine atoms.
According to formula (I), R is suitably hydroxycarbonyl or a prodrug comprising a CrCe ester, for example an ethyl or tert-butyl ester. R is preferably hydroxycarbonyl. According to formula (I), R2, R2a, R3 and R3a independently are suitably CrCe alkyl or H and are preferably H. According to formula (I), Z is suitably the group According to formula (I), R4 and R4a are suitably C1-C6 alkyl or H, preferably H. According to formula (I), R5 is suitably aryl or heteroaryl, optionally substituted with one or two substituents selected from the group consisting of a group consisting of halogen, C Ce alkyl, Ci-Ce alkoxy, C 1 -C 6 perfluoroalkyl, C 1 -C 6 perfluoroalkoxy, CrCB tto alkyl and Ci-Ce aminoalkyl. R5 is preferably phenyl, naphthyl or isoquinolinyl and is more preferably phenyl or 7-isoquinolinyl, optionally substituted with one or two substituents selected from the group consisting of halogen, CrC6 alkyl, CrC6 alkoxy, Ci-C6 perfluoroalkyl, C1-C6 perfluoroalkoxy, C6 alkylthio and C6 aminoalkyl. According to formula (I), Y is suitably S, CH2 or O and X is suitably a direct bond or C1-C2 alkyl, for example CH2, or X is suitably S, CH2 or O, Y is suitably C1-C2 alkyl, for example CH2. When Z is a substituted 5-membered heteroaryl or heterocycloalkyl, Z is preferably the group wherein R6 and R7 are independently H, halogen, C1-C6 alkyl, C1-C6 alkoxy, perfluoroalkyl Ct-Ce, perfluoroalkoxy Ci-C6, cyano, Ci-Ce alkyl amino, C6 alkyl, thio, C3-C8 cycloalkyl, monocyclic heteroaryl, phenyl or 4-8 membered heterocycloalkyl. A preferred subgroup according to the present invention is represented by a compound of the formula (II): FonruJto (ll) in which R8 and R9 are independently H, halogen, Ci-Ce alkyl, perfluoroCalkyl Ci-Ce, perfluoroalkoxy Ci-Ce, Ci-Ce alkyl or CrC6 aminoalkyl; and R10 is H or Ci-Ce alkyl, for example ethyl or tere-butyl.
According to formula (II), R8 and R9 are suitably positioned in the ortho and para positions and suitably independently selected from H, bromo, chloro and aminomethyl.
Another preferred subgroup according to the present invention is represented by a compound of the formula (III); Fdfmuta (III) wherein R1 is H or dC6 alkyl, for example tere-butyl. Particularly preferred examples of the compounds of the formula (I) are: ε-butyl acetate (. {2 - [(4-bromophenyl) sulfanyl] ethyl} amino); ferc-butyl acetate (. {2 - [(4-chlorophenyl) sulfanyl] ethyl} amino); urea-butyl acetate. { [2- (2,4-dichlorophenoxy) ethyl] amino}; urea-butyl acetate (. {2 - [(4-chlorobenzyl) sulfanyl] ethyl} amino); urea-butyl acetate. { [2- (7-isoquinolinylsulfanyl) ethyl] amino}; ({2 - [(4-chlorophenyl) sulfanyl] ethyl} amino) acetic acid; ( {2 - [(4-Bromophenyl) sulfanyl] ethyl] amino) acetic acid; [(2- {[[4- (aminomethyl) phenyl] sulfanyl} ethyl) amino] acetic acid; acid { [2- (2,4-dichlorophenoxy) ethyl] amino} acetic; acid (. {2 - [(4-chlorobenz) sulfanyl] ethyl] amino) acetic acid; acid { [2- (7-isoquinolinylsulfanyl) ethyl] amino} acetic; ethyl (. {2 - [(4-chlorophenyl) sulfanyl] ethyl} amino) acetate; [2- (4-chloro-phenoxy) -propylamino] -acetic acid ferc-butylester; salt of (2- (4-chloro-phenoxy) -propylamino] -acetic acid hydrochloride; [2- (4-Methylsufanyl-phenylsufanyl) -ethylamino] -acetic acid ferc-butylester; [2- (4-Methylsufanyl-phenylsulfanyl) -ethylamino] -acetic acid hydrochloride salt; (4-phenyl-butylamino) -acetic acid methyl ester; 4-phenylbutylamino acetic acid hydrochloride salt; and [2- (3-chloro-phenoxy) -butylamino] -acetic acid; dihydrochloride. Particularly preferred compounds of the invention include those in which each variable in Formula (I) is selected from the appropriate and / or preferred groups for each variable. Even the most preferred compounds of the invention include those in which each variable in Formula (I) is selected from the most preferred groups for each variable. It will be appreciated that certain compounds within the invention are novel and, therefore, these compounds or one of their pharmaceutically acceptable salts, solvates, polymorphisms or prodrugs, form yet another aspect of the present invention. The invention also relates to pharmaceutical compositions comprising the compounds and their use as a medicament. In the above definitions, halo means fluoro, chloro, bromo or iodo. The alkyl and alkoxy groups, which contain the required number of carbon atoms, except where indicated, may be unbranched or branched chain. Examples of alkyl include methyl, ethyl, n-propyl, i- propyl, n-butyl, i-butyl, sec-butyl and t-butyl. Examples of alkoxy include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, sec-butoxy and t-butoxy. 4-8 membered heterocycloalkyl, when used herein, refers to a single ring system containing at least one ring heteroatom independently selected from O, S and N. 4-12 membered heterocycloalkyl, when used herein, it refers to a single or condensed ring system containing at least one ring heteroatom independently selected from O, S and N. Thus, a polycyclic fused ring system containing one or more saturated carbocyclic rings , partially unsaturated or aromatic is within the definition of 4-12 membered heterocycloalkyl, as long as the system also contains at least one fused ring containing at least one of the aforementioned heteroatoms. Suitable heterocyclyl groups include pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydropyranyl, pyranyl, thiopyranyl, aziridinyl, oxyranyl, methylenedioxyl, chromenyl, isoxazolidinyl, 1,3-oxazolidin-3-yl, isothiazolidinyl, 1,3-thiazolidin-3-yl, , 2-pyrazolidin-2-yl, 1,3-pyrazolidin-1-yl, piperidinyl, thiomorpholinyl, 1,2-tetrahydrothiazin-2-yl,, 3-tetrahydrothiazin-3-yl, tetrahydrothiadiazinyl, morpholinyl, 1,2-tetrahydrodiazin-2-yl, 1,3-tetrahydrodiazin-1-yl, tetrahydroazepinyl, piperazinyl, chromanyl, etc. Heteroaryl, when used herein, refers to a simple or condensed aromatic ring containing at least one ring heteroatom independently selected from O, S and N. Therefore, a A polycyclic condensed ring system containing one or more saturated, partially unsaturated or aromatic condensed carbocyclic rings is within the definition of heteroaryl, provided that the system also contains at least one fused aromatic ring containing at least one of the heteroatoms already mentioned. Suitable heteroaryl groups include furyl, thienyl, thiazolyl, pyrazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrrolyl, triazolyl, tetrazolyl, imidazolyl, 1,3-oxadiazolyl, 1,4-oxadiazolyl, 1,2,3-oxadiazolyl. , 1, 3,5-thiadiazolyl, 1,2,3-thiadiazolyl, 1,4-thiadiazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, 1,2,4-triazinyl, 1,2,3-triazinyl, 1 , 3,5-triazinyl, pyrazolo [3,4-b] pyridinyl, cinolinyl, pteridinyl, pulinyl, 6,7-dihydro-5H- [1] pyrindinyl, benzo [b] thiophenyl, 5, 6, 7, 8- tetrahydro-quinolin-3-yl, benzoxazolyl, benzothiazolyl, benzisothiazolyl, benzisoxazolyl, benzimidazolyl, tianaphtenyl, isothianaphtenyl, benzofuranyl, isobenzofuranyl, isoindolyl, indolyl, indolizinyl, indazolyl, isoquinolyl, quinolyl, phthalazinyl, quinoxalinyl, quinazolinyl, benzoxazinyl, etc. C3-C8 cycloalkyl, as used herein, refers to a saturated or partially unsaturated single carbocyclic ring system. C3-C12-cycloalkyl, as used herein, refers to a simple or condensed saturated or partially unsaturated carbocyclic ring system. Suitable cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl groups. Aryl, when used herein, refers to phenyl or naphthyl. p Biosterol carboxylic acid, when used herein, refers to a group functionally equivalent to a carboxylic acid. Such biosters include tetrazole, oxazolidinone, sulfonic acid, sulfinic acid, phosphonic acid, phosphinic acid, hydantoin, pyrrolidione, 3-isoxazolyl, etc. The present compounds can exist in unsolvated forms as well as in solvated forms, including hydrated forms. In general, solvated forms, including hydrated forms, which may contain isotopic substitutions (eg, D20, d6-acetone, d6-D SO), are equivalent to unsolvated forms and are included within the scope of the invention. present invention. Certain compounds of the present invention possess one or more chiral centers and each center may exist in the R or S configuration. The present invention includes all enantiomeric and epimeric forms, as well as their appropriate mixtures. The separation of diastereoisomers or cis and trans isomers can be achieved by conventional techniques, e.g. eg, fractional crystallization, chromatography or H.P.L.C. of a stereoisomeric mixture of a compound of the invention or a pharmaceutically acceptable salt or derivative thereof. An individual enantiomer of a compound of the invention can also be prepared from the corresponding optically pure intermediate or by resolution, as by H.P.L.C. of the corresponding racemate, using a suitable chiral support or by fractional crystallization of the diaesteroisomeric salts formed by reacting the corresponding racemate with an optically suitable base or acid, as appropriate. The present invention also includes all suitable isotopic variations of a compound of the invention or a pharmaceutically acceptable salt thereof. An isotopic variation of a compound of the invention or a pharmaceutically acceptable salt thereof is defined as one in which at least one atom is replaced with an atom having the same atomic number but an atomic mass different from the atomic mass usually found naturally . Examples of isotopes that can be incorporated into the compounds of the invention and their pharmaceutically acceptable salts include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as 2H, 3H, 13C, 14C, 15N, 170 , 80, 31P, 32P, 35S, 18F and 36CI, respectively. Certain isotopic variations of the compounds of the invention and their pharmaceutically acceptable salts, for example, those into which a radioactive isotope, such as 3H or 4C, is incorporated, are useful in studies of tissue distribution of substrate and / or drug. Particularly preferred are the tritiated isotopes, i.e., 3H, and carbon-14, ie, C, for their ease of preparation and detectability. In addition, substitution with isotopes such as deuterium, i.e., 2H, can produce certain therapeutic advantages that arise from increased metabolic stability, for example, increased half-life in vivo or reduced dosage requirements and consequently may be preferred in some circumstances. The isotopic variations of the compounds of the invention and their salts Pharmaceutically acceptable compounds of the present invention can generally be prepared by conventional methods, such as the illustrative methods or the preparations described in the Examples and Preparations discussed below, using appropriate isotopic variations of the appropriate reagents. The pharmaceutically acceptable salts of the compounds of the formula (I) may be salts of appropriate non-toxic inorganic or organic bases or acids. Suitable acid addition salts are the hydrochloride / chloride, bromohydrate / bromide, hydroiodide / iodide, sulfate, bisulfate, nitrate, phosphate, hydrogen phosphate, acetate, fumarate, aspartate, besylate, bicarbonate / carbonate, camsylate, D salts. and L-lactate, D and L-tartrate, edisilate, mesylate, malonate, orotate, gluceptate, methylsulfate, stearate, glucuronate, 2-napsylate, tosylate, hibenzarate, nicotinate, isethionate, malate, maleate, citrate, gluconate, succinate, saccharate, benzoate, esylate and pamoate. Suitable base salts are formed from bases that form non-toxic salts and examples are the sodium, potassium, aluminum, calcium, magnesium, zinc, choline, diolamine, olamine, arginine, glycine, tromethamine, benzathine, lysine salts. , meglumine and diethylamine. Salts with quaternary ammonium ions can also be prepared with, for example, tetramethylamino ion. The compounds of the invention can also be formed as a zwitterion.
A suitable salt of the compounds of the present invention is the hydrochloride salt. For a review of suitable salts, see Berge et al. J. Pharm. Sci., 66, 1-19, 1977. Also included within the present scope of the compounds of the invention are their polymorphisms. Prodrugs of the aforementioned compounds are included within the scope of the present invention. The effectiveness of an orally administered drug depends on the efficient transport of the drug in the mucosal epithelium and its stability in the entero-hepatic circulation. Drugs that are effective after parenteral administration but less effective orally, or whose half-life in plasma is considered too short, can be chemically modified to a prodrug form. A prodrug is a drug that has been chemically modified and may be biologically inactive at its site of action, but which may be degraded or modified by one or more enzymatic or other in vivo processes to the main bioactive form. This drug or chemically modified prodrug should have a pharmacokinetic profile different from the main one, allowing easier absorption in the mucosal epithelium, better formulation and / or saline stability, improved systemic stability (for an increase in plasma half-life, for example). These chemical modifications can be (1) Derivatives of ester or amide that can be cleaved by, for example, esterases or lipases. For ester derivatives, the ester is derived of the carboxylic acid part of the drug molecule through known means. For amide derivatives, the amide may be derived from the carboxylic acid part or the amine part of the drug molecule through known means. (2) Peptides that can be recognized by specific or non-specific proteinases. A peptide can be coupled to the drug molecule via the formation of an amide bond with the amine or carboxylic acid part of the drug molecule through known means. (3) Derivatives that accumulate in a site of action through membrane selection of a prodrug form or modified prodrug form. (4) Any combination of 1 to 3. Those skilled in the art will further appreciate that certain remains, known in the art as "pro-moieties", for example as described in "Design of Prodrugs" by H Bundgaard (Elsevier ) 1985, can be arranged in appropriate functionalities when said functionalities are present in the compounds of the invention also to form a "prodrug". In addition, certain compounds of the invention can act as prodrugs of other compounds of the invention. All protected derivatives and prodrugs of the compounds of the invention are included within the scope of the invention. Research has shown that oral absorption of certain drugs can be increased by the preparation of quaternary salts "weak". Quaternary salt is called a "weak" quaternary salt because, unlike normal quaternary salts, p. eg, R-N + (CH3) 3, can release the active drug in hydrolysis. The "weak" quaternary salts have useful physical properties compared to the basic drug or its salts. The solubility in water can be increased, in comparison with other salts, such as hydrochloride, but the most important thing is that there can be an increase in the absorption of the drug in the intestine. The increased absorption is probably due to the fact that the "weak" quaternary salt possesses surfactant properties and is capable of forming micelles and pairs of non-ionized ions with bile acids, etc., which are capable of penetrating the intestinal epithelium more efficiently. The prodrug, after absorption, is rapidly hydrolyzed with the release of the main active drug. Amyloacyl-glycolic and lactic esters are known as amino acid prodrugs (Wermuth C.G., Chemistry and Industry, 1980: 433-435). The carbonyl group of the amino acids can be esterified by known means. Prodrugs and weak drugs are known in the art (Palomino E., Drugs of the Future, 1990; 15 (4): 361-368). The last two citations are incorporated herein by reference. The invention also relates to the therapeutic use of the present compounds as agents for treating or alleviating the symptoms of neurodegenerative disorders. Such neurodegenerative disorders include, for example, Alzheimer's disease, Huntington's disease, Parkinson's disease and amyotrophic lateral sclerosis. The present invention also covers treating neurodegenerative disorders termed acute brain injury. These include, but are not limited to: stroke, head injury, and asphyxia. Stroke refers to a cerebrovascular disease and may also be referred to as stroke (CVA) and includes acute thromboembolic stroke. Strokes include both focal and global ischemia. In addition, transient cerebral ischemic attacks and other cerebrovascular problems accompanied by cerebral ischemia are included. These vascular disorders can occur in a patient undergoing endarterectomy of the carotid specifically or other cerebrovascular or vascular surgical procedures in general, or diagnostic vascular procedures, including cerebral angiography and the like. Other incidents are head trauma, spinal trauma or injury spinal general anoxia, hypoxia, hypoglycemia, hypotension as well as similar injuries seen during procedures from embole, hyperfusion, and hypoxia. The present invention would be useful in a range of incidents, for example, during cardiac bypass surgery, in incidents of intracranial hemorrhage, in perinatal asphyxia, in cardiac arrest and epileptic status. An experienced practitioner will be able to determine the appropriate situation in which subjects are susceptible or at risk of, for example, stroke, as well as stroke by administration through the methods of the present invention.
The compounds of the present invention are useful for the general treatment of pain, particularly neuropathic pain. Physiological pain is an important protective mechanism designed to warn of the danger of potentially harmful stimuli from the external environment. The system works through a specific set of primary sensory neurons and is exclusively activated by noxious stimuli via peripheral transduction mechanisms (Illan 1999 Prog. Neurobio 57: 1-164 for an integrative review). These sensory fibers are known as nociceptors and are characterized by small diameter axons with slow driving speeds. The nociceptors encode the intensity, duration and quality of the noxious stimuli and, by virtue of their topographically organized projection towards the spinal cord, the location of the stimulus. Nociceptors are found in the nociceptive nerve fibers of which there are two main types, A-delta fibers (myelinated) and C fibers (non-myelinated). The activity generated by the nociceptor contribution is transferred after the processing of the complex in the dorsal horn, either directly, or via nuclei of the brainstem to the ventrobasal thalamus and then to the cortex, in which the sensation of pain is generated. Severe acute pain and chronic pain may comprise the same pathways as pathophysiological procedures and, as such, provide a protective mechanism and contribute instead to weaken the symptoms associated with a wide range of disease states. Pain is a characteristic of many traumatic and disease states. When a substantial injury occurs, via a disease or trauma to the body tissue, the activation characteristics of the nociceptor are altered. There is a sensitization in the periphery, locally around the lesion and centrally where the nociceptors end. This leads to hypersensitivity at the site of damage and in nearby normal tissue. In acute pain, these mechanisms can be useful and allow the repair procedures to take place and the hypersensitivity to return to its normal state once the lesion has healed. However, in many states of chronic pain, hypersensitivity outgrows the healing process and this is usually due to injury to the nervous system. This injury often leads to a maladaptation of the afferent fibers (Woolf & amp;; Salter 2000 Science 288: 1765-1768). Clinical pain is present when there is discomfort and abnormal sensitivity between the patient's symptoms. Patients tend to be quite heterogeneous and may present different symptoms of pain. There are a number of typical pain subtypes: 1) dull pain, which may be weak, burning or throbbing; 2) exaggerated responses of pain to noxious stimuli (hyperalgesia); 3) pain is produced by normally innocuous stimuli (allodynia) (eyer et al., 1994 Textbook of Pain 13-44). Although patients with back pain, arthritic pain, CNS trauma or neuropathic pain may have similar symptoms, the underlying mechanisms are different and, consequently, may require different treatment strategies. Therefore, pain can be divided into a number of different areas due to different pathophysiologies, including nociceptive, inflammatory, neuropathic pain, etc. It has been to observe that some types of pain have multiple etiologies and, therefore, can be classified in more than one area, p. eg, back pain, cancer pain may have inflammatory and neuropathic nociceptive components. Nociceptive pain is induced by a tissue injury or by intense stimuli with the potential to cause injury. Pain afferents are activated by the transduction of stimuli from the nociceptors at the site of the lesion and sensitize the spinal cord in its terminal part. They are then transmitted through the medullar pathways to the brain, where pain is perceived (Meyer et al., 1994 Textbook of Pain 13-44). The activation of the nociceptors activates two types of afferent nerve fibers. A-delta myelinated fibers are rapidly transmitted and are responsible for the sensations of sharp, throbbing pain, while non-myelinated C fibers are transmitted at a slower rate and transport the dull pain or fixed and continuous pain. Moderate to severe severe nociceptive pain is a prominent feature, for example, but not limited to, pain of muscle strains / sprains, postoperative pain (pain following any type of surgical procedure), post-traumatic pain, burns, heart attack, myocardium, acute pancreatitis and renal colic. Also acute pain syndromes related to cancer commonly due to therapeutic interactions, such as toxicity of chemotherapy, immunotherapy, hormonal therapy and radiotherapy. Moderate to severe nociceptive pain is a prominent feature of, but not limited to, cancer pain that may be associated with a tumor, (eg, bone pain, headache and facial pain, visceral pain) or associated with cancer therapy (eg, post-chemotherapy syndromes, chronic postoperative pain syndromes, posttraumatic syndromes) , back pain that may be due to herniated or ruptured intervertebral discs or abnormalities of the articular surfaces, sacroiliac joints, paraspinal muscles or the posterior longitudinal ligament. Neuropathic pain is defined as pain initiated or caused by a lesion or primary dysfunction in the central nervous system (definition of IASP). Nerve damage can be caused by trauma and disease and, therefore, the term 'neuropathic pain' encompasses many disorders with various etiologies. These include, but are not limited to, diabetic neuropathy, postherpetic neuralgia, back pain, cancer neuropathy, neuropathy induced by chemotherapy, HIV neuropathy, phantom limb pain, carpal tunnel syndrome, chronic alcoholism, hypothyroidism, trigeminal neuralgia, uremia, neuropathy induced by trauma or vitamin deficiencies. Neuropathic pain is pathological, as it has no protective function. It is often present after the cause has dissipated and commonly lasts for years, significantly decreasing the patient's quality of life (Woolf and Mannion 1999 Lancet 353: 1959-1964). Symptoms of neuropathic pain are difficult to treat, as they are often heterogeneous, even among patients with the same disease (Woolf &Decosterd 1999 Pain Supp 6: S141-S147; Woolf and Mannion 1999 Lancet 353: 1959-1964). They include spontaneous pain, which may be continuous, or paroxysmal or abnormal evoked pain, such as hyperalgesia (increased sensitivity to the noxious stimulus) and allodynia (sensitivity to a normally harmless stimulus). The inflammatory process is a complex series of biochemical and cellular events activated in response to tissue injury or the presence of foreign substances, resulting in inflammation and pain (Levine and Taiwo 1994: Textbook of Pain 45-56). Arthritic pain makes up the majority of the population of inflammatory pain. Rheumatoid disease is one of the most common chronic inflammatory conditions in developed countries and rheumatoid arthritis (RA) is a common cause of disability. The exact etiology of RA is unknown, but current hypotheses suggest that both genetic and microbiological factors may be important (Grennan &; Jayson 1994 Textbook of Pain 397-407). It has been estimated that nearly 16 million Americans suffer from symptomatic osteoarthritis (OA) or degenerative joint disease, most of whom are over 60 years of age, and this figure is expected to rise to 40 million, as increase the age of the population, making it a public health problem of enormous magnitude (Houge &Mersfelder 2002 Ann Pharmacother, 36: 679-686; cCarthy et al, 20 1994 Textbook of Pain 387-395). Most patients with OA seek medical attention due to pain. Arthritis has a significant impact on psychosocial and physical function and is known to be the fundamental cause of disability in old age. Other types of inflammatory pain include, but are not limited to, inflammatory bowel diseases (Ell). Other types of pain include, but are not limited to; - Musculoskeletal disorders, including, but not limited to, myalgia, fibromyalgia, spondylitis, seronegative arthropathies (non-rheumatoid) arthropathies, non-articular rheumatism, dystrophinopathy, glycogenolysis, polymyositis, pyomyositis. - Central pain or 'thalamic pain, as defined by pain caused by injury or dysfunction of the nervous system, including, but not limited to, central post-stroke, multiple sclerosis, spinal cord injury, Parkinson's disease and epilepsy. - Cardiac and vascular pain, including, but not limited to, angina, myocardial infarction, mitral stenosis, pericarditis, Raynaud's phenomenon, sclerodoma, skeletal muscle ischemia. - Visceral pain and gastrointestinal disorders. The viscera encompass the organs of the abdominal cavity. These organs include the sexual organs, the spleen and part of the digestive system. The pain associated with the viscera can be neuropathic, nociceptive, as well as inflammatory and can be divided into visceral digestive pain and non-digestive visceral pain. Gastrointestinal (Gl) disorders that commonly occur include functional bowel disorders (TIF) and inflammatory bowel diseases (Ell). These Gl disorders include a wide range of disease states that are currently controlled only moderately, including, for TIF, gastroesophageal reflux, dyspepsia, irritable bowel syndrome (SIL) and functional abdominal pain syndrome (SDAF) and, for Eli, Crohn's disease, ileitis and ulcerative colitis, which produce all regular visceral pain. Other types of visceral pain include pain associated with dysmenorrhea, pelvic pain, cystitis, and pancreatitis. Few drugs that act selectively on hypersensitivity associated with Gl disorders are known (Farthing M.J. (1998) Drugs 56: 11-21). The treatments available for pain are divided into two main categories: (1) non-steroidal anti-inflammatory drugs, used to treat mild pain, but whose therapeutic use is limited by the adverse effects Gl (gastric erosion, peptide formation, inflammation of the duodenum and colon); (2) morphine and related opioids, used to treat moderate to severe pain, but whose therapeutic use is limited by undesirable side effects, including constipation, respiratory depression, abuse potential, and tolerance. - Headache, including, but not limited to, migraine, migraine with aura, migraine without aura, histamine headache, tension-type headache. - Orofacial pain, including, but not limited to, dental pain, temporomandibular myofascial pain. The compounds of the invention are also expected to be useful in the treatment of depression. Depression can be the consequence of an organic disease, secondary to the stress associated with a personal loss, or it can be idiopathic in origin. There is a marked tendency to the familiar appearance of some forms of depression that suggest a mechanical cause for at least some forms of depression. The diagnosis of depression is mainly made by the quantification of alterations in the mood of the patient. These evaluations of moods in general are performed by a physician or quantified by a neuropsychologist, using validated rating scales, the Hamilton Depression Rating Scale or the Brief Psychiatric Rating Scale. Many other scales have been developed to quantify and measure the degree of mood alterations in patients with depression, such as insomnia, difficulty concentrating, lack of energy, feelings of worthlessness and guilt. The standards for the diagnosis of depression, as well as all psychiatric diagnoses, are compiled in the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) called manual DSM-IV-R, published by the American Psychiatric Association. { American Psychiatric Association), 1994. In another aspect, the use of a compound of the formula (I) is provided in the manufacture of a medicament for the treatment of a disease selected from epilepsy, syncope, hypokinesia, cranial disorders, neurodegenerative disorders, depression, anxiety, panic, pain, irritable bowel syndrome, sleep disorders, osteoarthritis, arthritis rheumatoid, neuropathological disorders, visceral pain, functional bowel disorders, inflammatory bowel diseases, pain associated with dysmenorrhea, pelvic pain, cystitis and pancreatitis. As an alternative aspect, a method is provided for treating a disease selected from epilepsy, syncope, hypokinesia, cranial disorders, neurodegenerative disorders, depression, anxiety, panic, pain, irritable bowel syndrome, sleep disorders, osteoarthritis, rheumatoid arthritis, disorders neuropathological, visceral pain, functional bowel disorders, inflammatory bowel diseases, pain associated with dysmenorrhea, pelvic pain, cystitis and pancreatitis which comprises administering a therapeutically effective amount of a compound of the formula (I) to a mammal in need of such treatment.
The compounds of the present invention can be administered in combination, either separately, sequentially or simultaneously, with one or more other pharmacologically active agents. Suitable agents, particularly for the treatment of pain, include: (i) opioid analgesics, e.g. eg, morphine, heroin, hydromorphone, oxymorphone, levorphanol, levalorphan, methadone, meperidine, fentanyl, cocaine, codeine, dihydrocodeine, oxycodone, hydrocodone, propoxyphene, nalmefene, nalorphine, buprenorphine, butorphanol, nalbuphine and pentazocine; (I) Opioid antagonists, p. e.g., naloxone, naltrexone (i¡¡) nonsteroidal anti-inflammatory drugs (NSAIDs), p. eg, aspirin, diclofenac, difluinsal, etodolac, fenbufen, fenoprofen, fl ufen salt, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, meclofenamic acid, mefenamic acid, nabumetone, naproxen, oxaprozin, phenylbutazone, piroxicam, sulindac, tolmetin, zomepirac and their pharmaceutically acceptable salts; (iv) barbiturate sedatives, p. eg, amobarbital, aprobarbital, butabarbital, butabital, mephobarbital, metarbital, methohexital, pentobarbital, phenobartital, secobarbital, talbutal, teamilal, thiopental and their pharmaceutically acceptable salts; (v) benzodiazepines having a sedative action, e.g. eg, chlordiazepoxide, clorazepate, diazepam, flurazepam, lorazepam, oxazepam, temazepam, triazolam and their pharmaceutically acceptable salts; (vi) Hi antagonists having a sedative action, e.g. g., diphenhydramine, pyrilamine, promethazine, chlorpheniramine, chlorcyclizine and their pharmaceutically acceptable salts; (vii) various sedatives, such as glutethimide, meprobamate, methaqualone, dichloralphenazone and their pharmaceutically acceptable salts; (viii) skeletal muscle relaxants, p. g., baclofen, tolperisone, carisoprodol, chlorzoxazone, cyclobenzaprine, methocarbamol, orfrenadine and their pharmaceutically acceptable salts; (ix) NMDA receptor antagonists, p. metabolites (((+) - 3-hydroxy-N-methylmorphinan), ketamine, memantine, pyrroloquinoline quinone and cis-4- acid (phosphonomethyl) -2-piperidinecarboxylic acid and its pharmaceutically acceptable salts; (x) alpha-adrenergic active compounds, p. eg, doxazosin, tamsulosin, clonidine and 4-amino-6,7-dimethoxy-2- (5-methanesulfonamido-1, 2,3,4-tetrahydroisoquinol-2-yl) -5- (2-pyridyl) quinazoline; (xi) tricyclic antidepressants, p. eg, desipramine, imipramine, amitriptyline and nortriptyline; (xií) anticonvulsants, p. eg, carbamazepine, valproate, lamotrigine; (xiii) serotonin reuptake inhibitors, p. eg, fluoxetine, paroxetine, citalopram and sertraline; (xiv) Mixed serotonin-noradrenaline reuptake inhibitors, p. eg, milnacipran, venlafaxine and duloxetine; (xv) noradrenaline reuptake inhibitors, p. eg, reboxetine; (xvi) Tachykinin (NK) antagonists, particularly Nk-3, NK-2 and NK-1, p. eg, antagonists, (aR, 9R) -7- [3,5bis (trifluoromethyl) benzyl] -8,9,10,11-tetrahydro-9-methyl-5- (4-methylphenyl) -7H - [1, 4] diazocino [2, 1 -g] [1, 7] naphthyridine-6-13-dione (TAK-637), 5 - [[(2R, 3S) -2 - [(1R) -1 - [3,5-bis (trifluoromethyl) phenyl] ethoxy-3- (4-fluorophenyl) -4-morpholinyl] methyl] -1,2-dihydro-3H-1, 2,4-triazol-3-one (MK) -869), lanepitant, dapitant and 3 - [[2-methoxy-5- (trifluoromethoxy) phenyl] methylamino] -2-phenyl-piperidine (2S.3S); (xvü) muscarinic antagonists, p. Oxybutyn, tolterodine, propiverine, tropsium chloride and darifenacin; (xviii) COX-2 inhibitors, p. eg, celecoxib, rofecoxib and valdecoxib; (xix) non-selective COX inhibitors (preferably with Gl protection), p. e.g., nitroflurbiprofen (HCT-1026); (xx) analgesics of coal tar, in particular, paracetamol; (xxi) neuroleptics, such as droperidol; (xxii) vanilloid receptor agonists, p. eg, resinferatoxin; (xxiii) beta-adrenergic compounds, such as propranolol; (xxiv) local anesthetics, such as mexiletine, lidocaine; (xxv) Corticosteroids, such as dexamethasone; (xxvi) serotonin receptor agonists and antagonists; (xxvii) cholinergic (nicotinic) analgesics; and (xxviii) miscellaneous agents such as Tramadol®; The combinations of the compounds of the present invention and other therapeutic agents can be administered separately, sequentially or simultaneously. Therefore, the present invention extends to a kit comprising a compound of the formula (I), one or more other therapeutic agents, such as those already mentioned, and a suitable container. The biological activity of the compounds of the invention can be measured in a radioligand binding assay, using [3H] gabapentin and the a ^ d subunit derived from porcine brain tissue (Gee N.S., Brown J.P., Dissanayake V.U.K., Offord J., Thurlow R., Woodruff G.N., J. Biol. Chem., 1996; 271: 5776-5879). The results can be expressed in terms of binding affinity a2d in μ? or nM. The compounds of the invention can be administered alone or in combination with other drugs, but in general they will be administered in admixture with pharmaceutically suitable excipients / s, divalent / s or vehicles / s, selected according to the route of administration that is intended for and according to standard pharmaceutical practice. The term "excipient" is used herein to describe any ingredient other than the compound of the invention. If appropriate, auxiliaries can be added. The auxiliaries are preservatives, anti-oxidants, flavorings or colorants. The compounds of the invention can be administered in a composition of the immediate, delayed, modified, sustained, pulsed or controlled type. The compounds of the formula (I) can be administered, for example, but not limited to, by the following routes: oral, buccal or sublingual in the form of tablets, capsules, multi and nanoparticles, liquids, gels, films. (including muco-adhesives), powders, ovules, elixirs, dragees (filled with liquid), chews, solutions, suspensions and aerosols. The compounds of the formula (I) can also be administered as an osmotic dosage form or in the form of a high energy dispersion or as coated particles or in rapid dissolution or rapid disintegration dosage form, such as those described in Expert Opinion. n Therapeutlc Patents, ü (6), 981-986 by Liang and Chen (2001). The compounds of the formula (I) can be administered as crystalline or amorphous products. They can be obtained, for example, as plugs, films or solid powders, through methods such as precipitation, crystallization, lyophilization, spray drying or evaporative drying. Microwave or radiofrequency drying can also be used for this purpose. Suitable formulations of the compounds of the formula (I) may be in a hydrophilic or hydrophobic matrix, ion exchange resin complex, in coated or uncoated form and other types described in the international publication US 6,106,864, as appropriate. want. Said pharmaceutical compositions, for example, the tablets, may contain excipients, such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dibasic calcium phosphate, glycine and starch (preferably corn starch, potato or tapioca), mannitol, disintegrants such as sodium starch glycolate, croscarmellose sodium and certain complex silicates and granulation binders, such as polyvinylpyrrolidone, hydroxypropylmethylcellulose (HP C), triglycerides, hydroxypropylcellulose (HPC), beryllite sucrose, sorbitol, gelatin and acacia. Additionally, lubricating agents may be added to the solid compositions, for example magnesium stearate, stearic acid, glycerylbehenate, PEG and talc or wetting agents, such as sodium lauryl sulfate or preservatives, antioxidants, flavorings and colorants. Additionally, polymers such as carbohydrates, phospholipids and proteins may be included.
The dosage formulations with dispersion or rapid dissolution. { Fast dispersing or dissolving dosage formulations or FDDF) may contain the following ingredients: aspartame, acesulfame potassium, citric acid, croscarmellose sodium, crospovidone, diascorbic acid, ethyl acrylate, ethylcellulose, gelatin, hydroxypropylmethylcellulose, magnesium stearate, mannitol, methylmethacrylate, peppermint flavoring, polyethylene glycol, fumed silica, silicon dioxide, sodium starch glycolate, sodium silyl fumarate, sorbitol or xylitol. The terms "disperse" or "dissolve", as used herein to describe FDDF, depend on the solubility of the substance of the drug, ie, when the substance of the drug is insoluble, a fast dispersing dosage form can be prepared. When the substance of the drug is soluble, a rapid dissolution dosage form can be prepared. Solid dosage forms, such as tablets, are made using standard procedures known to a chemist in formulations, for example, by direct compression, wet or melt granulation, extrusion or melt freezing. The tablet cores, which may be single layer or multiple layers, may be coated with appropriate coatings known in the art. Solid formulations for oral administration can be formulated for immediate and / or modified release. Modified release formulations include delayed, sustained, pulsed, controlled, directed and programmed release. Release formulations modified suitable for the purposes of the invention are described in U.S. Patent No. 6,106,864. Details of other suitable release technologies, such as high energy dispersions and osmotic and coated particles can be found in Verma et al, Pharmaceutical Technology On-line, 25 (2), 1-14 (2001). Solid compositions of a similar type can also be employed as fillers in capsules such as gelatin, starch or HPMC capsules. Preferred excipients in this regard include lactose, starch, a cellulose, milk sugar or high molecular weight polyethylene glycols. The liquid compositions can be used as filters in soft or hard capsules, such as gelatin capsules, and typically comprise a carrier, for example water, ethanol, propylene glycol, methylcellulose or a suitable oil, and one or more emulsifying agents and / or preservatives. suspension. For aqueous and oily suspensions, solutions, syrups, and / or elixirs, the compounds of the invention can be combined with various sweetening or flavoring agents, dyes or coloring dyes, with emulsifying and / or suspending agents and with diluents such as water, ethanol, propylene glycol, methylcellulose, alginic acid or sodium alginate, glycerin, oils, hydrocolloid agents and their combinations. Also, formulations containing these compounds and excipients may be presented as a dry product for reconstitution with water or other suitable vehicles before use.
Preparations in liquid form include solutions, suspensions, syrups, elixirs and emulsions, for example, water or aqueous propylene glycol solutions. For liquid preparations, parenteral injection can be formulated in aqueous polyethylene glycol solution. Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizing and thickening agents, as desired. Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose and other known suspending agents. The compounds of the present invention can also be administered by injection, that is, intravenously, intramuscularly, intracutaneously, intraduodenally or intraperitoneally, intra-arterial, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intraspinal or subcutaneous. Suitable devices for parenteral administration include needles (including microneedles), injectors, needleless injectors, infusion or implant injection techniques. For such parenteral administration, they are optimally used in the form of a sterile aqueous solution, suspension or emulsion (or system which may include micelles) which may contain other substances known in the art, for example, salts or sufficient carbohydrates, such as glucose, to make that the dissolution is sotonic with the blood. Aqueous solutions must be adequately buffered (preferably up to a pH between 3 and 9), if necessary. For some forms of parenteral administration they can be used in the form of a sterile non-aqueous system, such as fixed oils, including mono or diglycerides and fatty acids, including oleic acid. The preparation of suitable parenteral formulations under sterile conditions, for example lyophilization, is easily accomplished by standard pharmaceutical techniques known to those skilled in the art. Alternatively, the active ingredient may be in dry form for use in conjunction with a suitable vehicle such as sterile, pyrogen-free water. The solubility of the compounds of the formula (I) used in the preparation of parenteral solutions can be increased with the use of appropriate formulation techniques, such as the incorporation of solubility enhancing agents. Formulations for parenteral administration can be formulated to be immediate and / or modified release. Therefore, the compounds of the formula (I) can be formulated into a more solid form for administration as an implanted delivery drug that provides long-term release of the active compound. In addition, the compounds of the present invention can be administered intranasally or by inhalation. Conveniently, they are administered in the form of a dry powder (either alone, as a mixture, for example a dry mixture with lactose, or a particle of mixed components, for example with phospholipids) from a powder inhaler or a presentation for aerosol spray from a pressurized container, pump, sprayer, atomizer (preferably an atomizer using electrohydrodynamics to produce a clear vapor) or a nebulizer, with or without the use of a suitable propellant, e.g. g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, a hydrofluoroalkane such as 1,1,1-tetralfuoroethane (HFA134A [brand]) or 1, 1, 1, 2,3,3,3-heptafluoropropane (HFA 227EA [brand] )), carbon dioxide, another perfluorinated hydrocarbon, such as Perflubron [brand name] or another suitable gas. The pressurized container, pump, sprayer, atomizer, or nebulizer may contain a solution or suspension of the active compound, for example, using a mixture of ethanol (optionally aqueous ethanol) or a suitable agent to disperse, solubilize or extend the release and the propellant as the solvent, which may additionally contain a surfactant, such as sorbitan trioleate or an acid 15 oligoláctico. Capsules, ampoules and lozenges (made, for example, of gelatin or HPMC) for use in an inhaler or insufflator can be formulated to contain a powder mixture of the compound of the invention, a suitable powder base, such as lactose or starch. and a performance modifier, such as l-leucine, mannitol or magnesium stearate. 20 In the case of aerosols and dry powder inhalers, the unit dose is determined by a valve that supplies a measured quantity.
Prior to use, in a dry powder formulation or suspension formulation for inhalation, the compound of the invention is micronized to a size suitable for administration by inhalation (typically considered to be less than 5 microns). Micronization can be achieved through any suitable grinding method, for example, spiral jet grinding, fluidized bed jet grinding, supercritical fluid processing to form nanoparticles, high pressure homogenization or spray dehydration. A solution formulation suitable for use in an atomizer that uses electrohydrodynamics to produce a clear vapor may contain between 1 pg and 10 mg of the compound of the invention per actuation and the actuation volume may vary between 1 μ? and 100μ ?. A typical formulation may comprise a compound of the formula (I), propylene glycol, sterile water, ethanol and sodium chloride. Alternative solvents can be used instead of propylene glycol, for example glycerol or polyethylene glycol. Formulations for inhaled / intranasal administration can be formulated to be immediate and / or modified release. Alternatively, the compounds of the invention can be administered topically to the skin or mucosa, either dermally or transdermally, for example, in the form of a gel, hydrogel, lotion, solution, cream, ointment, powder, dressing, foam, film , skin patch, wafer, implant, sponge, fiber, bandage, microemulsion and their combinations Liposomes can also be used. For such applications, the compounds of the formula (I) can be suspended or dissolved in, for example, a mixture with one or more of the following: mineral oil, liquid petrolatum, white petrolatum, glycerin, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax, fixed oils, including synthetic mono or diglycerides and fatty acids, including oleic acid, water, sorbitan monostearate, a polyethylene glycol, liquid paraffin, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, alcohols such as ethanol. Alternatively, penetration enhancers may be used, see, for example, J. Pharm. ScL, 88 (10), 955-958 by Finnin and Morgan (October 1999). The following polymers, carbohydrates, proteins, phospholipids can also be used in the form of nanoparticles (such as niosomes or liposomes), or suspended or dissolved. In addition, they can be administered using iontophoresis, electroporation, phonophoresis and sonophoresis. Other means of topical administration include administration by iontophoresis, electroporation, phonophoresis, sonophoresis and needleless or microneedle injection. Formulations for topical administration can be formulated to be immediate and / or modified release. Alternatively, the compounds of the invention can be administered rectally, for example in the form of a suppository, pessary or enema. They can also be administered through the vaginal route. For example, although not limited to the following presentations, these compositions can be prepared by mixing the drug with suitable non-irritating excipients, such as cocoa butter, synthetic glyceride esters or polyethylene glycols, which are solid at ordinary temperatures, but which are liquified and / or dissolved in the cavity to release the drug. Formulations for rectal / vaginal administration can be formulated to be immediate and / or modified release. The compounds of the invention can also be administered directly to the eye or ear. For ocular and aural administration, the compounds of the formula (I) can be formulated as suspensions or solutions formulated as micronized in sterile isotonic saline with adjusted pH. A polymer, such as a cross-linked polyacrylic acid, polyvinyl alcohol, hyaluronic acid, a cellulosic polymer (eg, hydroxypropylmethylcellulose, hydroxyethylcellulose or methylcellulose), or a heteropolysaccharide polymer (eg, gellan gum) may be added. ). Alternatively, they can be formulated into an ointment such as petroleum jelly or mineral oil, incorporated into implants, wafers, drops, biodegradable lenses (eg sponges with absorbable gel, collagen) or non-biodegradable lenses (eg, siliceous) or administered via particulate or vesicular systems, such as niosomes or liposomes. The formulations may optionally be combined with a preservative, such as benzalkonium chloride. In addition, they can be administered using iontophoresis.
Formulations for ocular / aural administration can be formulated to be immediate and / or modified release. The compounds of the invention can also be used in combination with soluble macromolecular entities, such as cyclodextrin or polymers containing polyethylene glycol to improve their solubility, dissolution ratio, taste masking, bioavailability and / or stability. Drug-cyclodextrin complexes are generally useful for most dosage forms and routes of administration. Both inclusion and non-inclusion complexes can be used. As an alternative to direct complex formation with the drug, the cyclodextrin can be used as an auxiliary additive, e.g. eg, as a vehicle, diluent or solubilizer. Alpha, beta and gamma-cyclodextrins are most commonly used and suitable examples are described in international publications WO-A-91/11172, WO-A-94/02518 and WO-A-98/55148. The term "administer" includes delivery by viral and non-viral techniques. Viral administration mechanisms include, but are not limited to, adenoviral vectors, adeno-associated viral vectors (AAV), herpes virus vectors, retroviral vectors, lentiviral vectors and baculovial vectors. Non-viral delivery mechanisms include lipid-mediated transfection, liposomes, immunoliposomes, lipofectin, cationic facial amphiphiles (CFA), and combinations thereof. Routes for such management mechanisms include, but are not limited to, this, the mucous, nasal, oral, parenteral, gastrointestinal, topical or sublingual routes. The pharmaceutical preparation preferably has a unit dose form. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, wherein the package contains discrete quantities of the preparation, such as tablets, capsules and powders packed in vials or ampoules. In addition, the unit dosage form can be a capsule, tablet, wafer or lozenge itself, or it can be an appropriate amount of any of these in packaged form. The amount of the active component in a unit dose preparation can be varied or adjusted between 0.1 mg and 1 g according to the particular application and potency of the active component. In medical use, the drug can be administered three times a day, for example, in capsules of 100 or 300 mg. In therapeutic use, the compounds used in the pharmaceutical method of the present invention are administered in the initial dose of from about 0.01 mg to about 100 mg / kg daily. A daily dose range of about 0.01 mg to about 100 mg / kg is preferred. The doses, however, may be varied depending on the patient's requirements, the severity of the condition being treated and the compound being used. The determination of the appropriate dose for a particular situation is within the skill of the person skilled in the art. In general, treatment starts with smaller doses that are lower than the optimum dose of the compound. Thereafter, the dose is increased in small increments until the optimum effect is reached according to the circumstances. For convenience, the total daily dose can be divided and administered in portions during the day, if desired. The pharmaceutical composition according to the present invention can, if desired, also contain one or more other compatible therapeutic agents. In particular, the composition can be combined with one or more compounds useful in the treatment of pain, such as those already mentioned. Therefore, the present invention features a pharmaceutical composition comprising a compound of the formula (I), one or more other pharmacologically active agents and one or more pharmaceutically acceptable carriers. It is to be appreciated that all references herein to treatments include curative, palliative and prophylactic treatment. GENERAL METHODS The compounds of the formula (I) can be synthesized using the various methods set out below; According to a first and a second process, A and B, a compound of the formula (I) can be prepared by reacting a compound of the formula (IV) with a compound of the formula (V) or a compound of the formula (VI) with a compound of the formula (VII); wherein L is a suitable leaving group, such as a leaving group of halide, mesylate, tosylate or triflate or (= 0), in the presence of a suitable base such as potassium carbonate in a suitable solvent, such as dimethylformamide, or in the that L is (= 0), under reductive amination, using a suitable reducing agent, such as NaCNBH3 or Na (OAc) 3BH, an ester of glycoxalate such as ethyl glycoxalate, and a catalytic amount of an acid such as acetic acid in such a solvent as dichloromethane. Alternatively, according to a third method, C, a compound of the formula (I) can be prepared by deprotection of a compound of the formula (VIII); (vni) wherein PG is a suitable protecting group such as tert-butoxycarbonyl, acid-mediated hydrolysis of (VIII), using a strong acid suitable such as trifluoroacetic acid or hydrochloric acid in a suitable solvent, such as dioxane or dichloromethane. According to a fourth procedure, D, in which Z is Y is S, O or NH and X is a direct bond or C1-C2 alkyl, a compound of the formula (I) can be prepared according to scheme 1. Scheme 1 wherein L is a suitable leaving group such as a leaving group of halide, mesylate, tosylate or triflate. Typical reaction conditions; (i) Addition of an alkali metal salt, such as potassium carbonate, or an alkali metal hydride, such as sodium hydride a (IX) in a suitable solvent such as tetrahydrofuran at 0-25 ° C, with subsequent addition of (VII) and stirring at 0-100 ° C for 2-24 hours. (ii) Addition of an alkali metal salt such as potassium tert-butoxide, a strong organic base such as 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), or an alkali metal hydride such as sodium hydride, a (X) in tetrahydrofuran or an alcohol solvent such as fer-butanol, with subsequent addition of (XI) and reflux for 2-24 hours. Alternatively, according to a fifth process, E, wherein Z is R y Y and R 4 R * Y is S, O or NH, X is a direct bond or C 1 -C 2 alkyl and R 4a is H, a compound of the formula (I ) can be prepared according to scheme 2. Scheme 2 Typical reaction conditions; Addition of an alkali metal salt such as potassium carbonate, or an alkali metal hydride such as sodium hydride a (XIII) in a suitable solvent such as tetrahydrofuran, acetonitrile or dimethylformamide at 0-25 ° C, with subsequent addition of (XI) and stirring at 0-100 ° C for 2-24 hours. Alternatively, according to a sixth procedure, F, in Y is S or O, X is a direct bond and R4 is H, a compound of the formula (I) can be prepared according to Scheme 3. Scheme 3 wherein L is a suitable leaving group, such as an aluro, mesylate, tosylate or triflate group. Typical reaction conditions; (i) Addition of a base such as triethylamine to (XIV) and (VII) in a suitable solvent such as diethyl ether at 25 ° C, stirring for 18 hours. (ii) Protection of nitrogen by the addition of, for example, B0C2O, base such as sodium acetate in a suitable solvent such as dioxane at 25 ° C for 4 hours to produce (XV) - (iii) Addition of (XV) , triphenylphosphine, an azodicarboxylate such as diisopropydiazodicarboxylate and (XI) in a suitable solvent such as tetrahydrofuran, stirring at 25 ° C for 18 hours. According to a seventh procedure, G, a compound of the formula (I) can be prepared from a different compound of the formula (I), using standard techniques known in the art. For example, the compounds of the formula (I), wherein R1 comprises a carboxylic acid group can be prepared from the compound of the formula (I), in the that the corresponding position comprises a carboxyl ester group. The methods known in the art can be employed to facilitate the transformation of an ester to an acid such as acid hydrolysis, using, for example, trifluoroacetic acid or hydrochloric acid, base-mediated hydrolysis, using, for example, a metal hydroxide. alkali such as sodium hydroxide, or hydrogenation with a suitable catalyst such as palladium on carbon. Referring to the aforementioned general methods, the person skilled in the art will readily understand that when protecting groups are present, these will generally be interchangeable with other protecting groups of a similar nature, e.g. For example, when it is described that an amine is being protected with a tert-butoxycarbonyl group, it can easily be exchanged with any suitable amine protecting group. The compounds (IV) - (XV) can be prepared by methods of literature known to the person with experience in the technical field. The person skilled in the art will readily understand that the particular steps in the general methods previously presented herein can be suitably combined in any other that is not shown, in order to provide a compound according to the present invention.
Therefore, in summary, the invention provides: (i) a process for the preparation of a compound of the formula (I) or a pharmaceutically acceptable salt, solvate, polymorphism or prodrug thereof; (ii) a pharmaceutical composition that includes a compound of the formula (I) or a pharmaceutically acceptable salt, solvate, polymorphism or prodrug thereof, together with a pharmaceutically acceptable excipient, diluent or carrier; (iii) a compound of the formula (I) or a pharmaceutically acceptable salt, solvate, polymorphism, prodrug or composition thereof for use as a medicament; (iv) the use of a compound of the formula (I) or one of its pharmaceutically acceptable salts, solvates, polymorphisms, prodrugs or compositions for the manufacture of a medicament for the treatment of any of the aforementioned conditions; (v) the use of a compound of the formula (I) or of one of its pharmaceutically acceptable salts, solvates, polymorphisms, prodrugs or compositions for the manufacture of a medicament for the treatment of any of the aforementioned conditions; (vi) a method of treating a mammal to treat any of the aforementioned conditions, including treating said mammal with an effective amount of a compound of the formula (I) or with one of its salts, solvates, polymorphisms, prodrugs or pharmaceutically acceptable compositions; (vii) a method for the treatment of any of the aforementioned conditions, comprising administering to a patient in need of said treatment, or simultaneously, sequentially or separately, a combination of a compound of the formula (I) and another agent for pain; (viii) the use of a combination of a compound of the formula (I) and another therapeutic agent for the manufacture of a medicament for the treatment of any of the aforementioned conditions; and (ix) a product containing a compound of the formula (I) and another therapeutic agent as a combined preparation for simultaneous, separate or sequential use in the treatment of any of the aforementioned conditions. The present invention is illustrated by the following examples and non-limiting intermediates. Example 1 Tert-butyl acetate (. {2 - [(4-bromophenyl) sulfanyl] ethyl} amino) A stirred mixture of 4-bromothiophenol (10 g, 53 mmol) and potassium tert-butoxide (7.11 g, 63.5 mmol) in 2-methyl-2-propanol (250 mL) was added. heated to 60 ° C for 30 minutes before adding the compound of Preparation 1 (12.8 g, 63.5 mmol) in portions. The reaction mixture was heated to 80 ° C for 5 hours and then concentrated to a thick syrup in vacuo. Water (250ml) and then 2M sodium hydroxide (10ml) were added until pH = 12. The organic phase was extracted with dichloromethane (3 x 250 mL), washed again with brine (150 mL), dried over magnesium sulfate and concentrated in vacuo to yield 16.6 g (90%) of light brown oil. . 1 H-NMR (400MHz, CDCl 3): 5 = 1.45 (s, 9H), 2.84 (t, 2H), 3.04 (t, 2H), 3.30 (s, 2H), 7.24 (d, 2H), 7.40 (d, 2H). MS (Electrospray): m / z [?? -] 348, [Mna +] 370, [2MH +] 715. EXAMPLE 2 Fer-butyl acetate (. {2 - [(4-chlorophenyl) sulfanyl] ethyl.}. Not me) To 3.8 g (26.3 mmol) of 4-chlorothiophenol in 100 ml of urea-butanol at room temperature and under a nitrogen atmosphere was added 3.1 g (27.6 mmol) of potassium erc-butoxide. The mixture was stirred for ten minutes and 5 g (24.8 mmol) of Preparation 1 was added, and the mixture was heated to reflux for 24 hours.The solvent was removed under reduced pressure and the yellow oily residue dissolved in diethyl ether (70 ml) and the title compound (7.1 g, 90%) was isolated by precipitation as the salt of hydrochloride by addition of 0.5M hydrochloric acid (50 ml), filtration and drying under reduced pressure. 1H-NMR (400MHz, CD3OD) d = 1.51 (s, 9H), 3.2-3.28 (m, 4H), 3.90 (s, 2H), 7.36-7.38 (d , 2H), 7.44-7.47 (d, 2H) LRMS (electrospray): m / z [MH +] 302; [Na +] 324 Example 3 Ferric-butyl acetate. { [2- (2,4-dichlorophenoxy) ethyl] amine} To 350 mg (1.44 mmol) of 2- (2,4-dichlorophenoxy) ethanamine and 0.2 ml (1.44 mmol) of triethylamine in 30 ml of dichloromethane were added, stirring at room temperature under an atmosphere of nitrogen, aliquots of 0.21 ml (1.44 mmol), every 30 minutes, of urea-butyl bromoacetate until the starting material was completely consumed. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel, eluting with dichloromethane: methanol: ama (95: 5.0.5) to yield the title compound (300 mg, 65%) as a colorless oil. 1 H-NR (400MHz, CDCl 3) d = 1, 42-1, 45 (s, 9H), 3.03-3.07 (t, 2H), 3.59 (s, 2H), 4.08-4 , 12 (t, 2H), 6.83-6.88 (d, 1 H), 7.14-7.18 (m, 1H), 7.34-7.37 (m, 1H).
EXAMPLE 4 I-butyl-butyl (. {2 - [(4-chlorobenzyl) sulfanyl] ethyl} amine) acetate To a solution of 4-chlorobenzylmercaptan (370 mg, 2.3 mmol) in ether-butanol (10 mL) under nitrogen, potassium urea-butoxide (140 mg, 1.2 mmol) was added and the reaction was heated to 50 ° C for 15 minutes. After cooling to room temperature, the oxazolidinone of Preparation 1 was added and the reaction was heated to reflux for 18 hours. The reaction was cooled to room temperature and the solvent was removed under reduced pressure. The residue was partitioned between water (10 ml) and dichloromethane (20 ml). The two phases were separated and the aqueous was washed with dichloromethane (20 ml). The combined organic extracts were washed with saturated aqueous sodium chloride (15 ml), they were filtered, dried over magnesium sulfate and evaporated under reduced pressure. The crude product was purified by chromatography on silica (20 g) eluting with a solvent gradient of pentane: diethylether (2: 1 by volume), changing to pentane: diethylether (1: 1 by volume) to yield the title compound as a colorless oil (246 mg, 62%) 1 H-NMR (400MHz, CDCl 3): d = 1, 39-1, 52 (s, 9H), 1, 95-2.11 (s, 1 H), 2 , 52-2.59 (t, 2H), 2.76-2.78 (t, 2H), 3.25-3.30 (s, 2H), 3.67-3.71 (s, 2H) , 7.23-7.30 (m, 4H). LRMS (electrospray): m / z [MNa +] 338 Example 5-Butyl-butyl acetate. { [2- (7-Isoquinolinylsulfanyl) ethyl] amine} The thiol of Preparation 8 (975 mg, 6.05 mmol) was suspended in rt-butanol (30 mL) and potassium fer-butoxide (675 mg, 6.015 mmol) was added. The mixture was heated to 60 ° C for 30 minutes and the reaction was cooled to RT. The oxazolidinone from Preparation 1 was added and the reaction was heated to reflux for 4 hours before leaving at room temperature overnight. The solvent was evaporated under reduced pressure and the residue was dissolved in dichloromethane (25 ml). The solution was washed with water (10 ml), saturated aqueous sodium chloride (10 ml), dried over magnesium sulfate and evaporated under reduced pressure. Chromatography on silica (20 g), eluting with pentane: diethylether (2: 1 by volume), afforded the title compound as a white waxy solid (317 mg, 20%). 1 H-NMR (400MHz, CDCl 3): d = 1, 42-1, 53 (s, 9H), 2.00-2.22 (s, 1 H), 2.93-2.99 (t, 2H) , 3.19-3.25 (t, 2H), 3.33-3.38 (s, 2H), 7.58-8.12 (m, 4H), 8.48-8.45 (m, 1 H), 9.16-9.20 (s, 1 H). LRMS (electrospray): m / z [MNa] 341 Example 6: (. {2 - [(4-chlorophenyl) sulfanyl] ethyl} amino) acetic acid 400 mg (1.18 mmol) of fer-t-butyl acetate (. {2 - [(4-chlorophenyl) sulfanyl] ethyl} amino) were dissolved / suspended (Example 2) in 10 ml of anhydrous hydrogen chloride. in dioxane solution and heated to 50 ° C for 1 hour. The solvent was removed under reduced pressure and the white solid residue was recrystallized from isopropyl alcohol to yield the title compound (250 mg, 86%). 1 H-NMR (400MHz, D20) d = 3.12-3.13 (s, 4H), 3.64 (s, 2H), 7.26-7.29 (d, 2H), 7.29- 7.32 (d, 2H) LRMS (electrospray): m / z [?? ÷] 246; [MNa +] 268; [MH] 244 Macroanalysis: Experimental: C, 42.50; H, 4.57; N, 4.79.
C10H12CINO2S.HCl requires C, 42.56; H, 4.64; N, 4.96 Example 7: (. {2 - [(4-Bromophenyl) sulfanyl] ethyl} amino) acetic acid Using the method of Example 6, ferc-butyl acetate (. {2 - [(4-bromophenyl) sulfanyl] ethyl} amino) was hydrolyzed (Example 1, 150 mg, 0.34 mmol), yielding 60 mg (61%) of the title compound. 1 H-NMR (400MHz, CD3OD): d = 3.26 (s, 4H), 3.94 (s, 2H), 7.38 (d, 2H), 7.51 (d, 2H). MS (Electrospray): m / z [MH *] 291, [M-] 289. Microanalysis; Experimental C, 36.46; H, 3.92; N, 4.25. CuHi6N02S, 1, 1 HCI requires C, 36.37; H, 4.0; N, 4.24 Example 8 [(2- {[[4- (Aminomethyl) phenyl] sulfanyl] ethyl] amino] acetic acid Using the method of Example 6, ferc-butyl acetate (. {2 - [(4-aminomethylphenol) sulfanyl] ethyl} amino) (30 mg, 0.076 mmol) was hydrolysed to yield the title compound ( 20 mg, 81%). 1H-NMR (400MHz, CD3OD): d = 3.30 (m, 4H), 3.94 (s, 2H), 4.11 (s, 2H), 7.46 (d, 2H), 7.53 (d, 2H). MS (Electrospray): m / z [MH +] 241, [MNa +] 263, [2MH +] 481, [M-] 239. Microanalysis: Experimental: C, 40.93; H, 5.72; N, 8.28. CiiHi6N202S, 2.3HCl requires C, 40.76; H, 5.69; N, 8.64. Example 9 acid. { [2- (2,4-dichlorophenoxy) ethyl] amino} acetic Using the method of Example 6, 300 mg (0.9 mmol) of fer-butyl acetate was hydrolysed. { [2-. { 2,4-dichlorophenoxy) ethyl] amino} (Example 3) to produce the title compound (58 mg, 22%) as a white solid. 1H-NM (400MHz, D6-DMSO) d = 3.39-3.43 (m, 2H), 3.97-3.98 (s, 2H), 4.36-4.40 (m, 2H) , 7.19-7.23 (d, 1 H), 7.37-7.42 (d, 1 H), 7.59-7.60 (s, 1 H) LRMS (thermospray): m / z [MH +] 264; [MNa +] 286; [MhT] 262 Microanalysis: Experimental C, 40.10; H, 4.00; N, 4.59. CioH NC C. HCI requires C, 39.96; H, 4.03; N, 4.66. EXAMPLE 10 Acid (. {2 - [(4-chlorobenzyl) sulfanyl] ethyl} amino) acetic acid The method of Example 6 was used to hydrolyze the amino ester of Example 4 (215 mg, 0.68 mmol) to yield the title compound as a white solid (138 mg, 68%) 1 H-NMR (400 MHz, CD3OD): d = 2.71-2.79 (t, 2H), 3.21-3.32 (s, 2H), 3.79-3.88 (s, 2H), 3.91-3.98 (s, 2H), 4.86-4.93 ( s, 3H), 7.29-7.41 (m, 4H).
LRMS (electrospray): m / z [MH *] 260, [MNa +] 282, [M-1] 258. Microanalysis: Experimental: C, 44.56; H, 5.17; N; 4.70. C11H14CINO2S.HCl requires C, 44.690; H, 5.10; N, 4.73. Example 11 Acid. { [2- (7-isoquinolinylsulfanyl) ethyl] amino} acetic The amino ester of Example 5 (240 mg, 0.755 mmol) was dissolved in dichloromethane (6 ml) and trifluoroacetic acid (2 ml) was added. The reaction was stirred at room temperature for 5 hours and then the solvent was removed under reduced pressure. The residue was triturated with diethyl ether to yield a pale yellow solid, where one half of it was dissolved in a minimum of water and purified by chromatography on MCI gel, eluting with a water: acetonitrile (100: 0) gradient. gradually to water: acetonitrile (80: 20). This produced the title compound (30 mg, 15%) as a white solid. 1 H-NMR (400MHz, CD 3 OD): d = 3.26-3.33 (t, 2H), 3.39-3.45 (t, 2H), 3.51-3.54 (s, 2H), 4.77-4.83 (s, 3H), 7.78-7.82 (m, 2H), 7.91-7.94 (s, 1H), 8.13-8.15 (s, 1 H), 8.41-8.43), 9.91-9.21 (s, 1 H). LRMS (electrospray): m / z [MH +] 263, [MNa + j 285, [M-1] 261. Mycroanalysis: Experimental, 55.94; H, 5.71; N, 9.89. C3H14 2O2S. H20 requires C, 55.70; H, 5.75; N, 9.99. Example 12 Ethyl (. {2 - [(4-chlorophenyl) sulfanyl] ethyl} amino) acetate To 600 mg (1.77 mmol) of tert-butyl acetate (. {2 - [(4-chlorophenyl) sulfanyl] ethyl} amino) (Example 2), dissolved / suspended in 10 ml of ethanol, they added 10 ml of anhydrous 4M hydrogen chloride in dioxane solution, and the mixture was heated to reflux for 30 minutes.
The solvent was removed under reduced pressure and the white solid residue was recrystallized from ethanol to yield the title compound (423 mg, 88%). 1H-NMR (400MHz, D20) d = 1, 08-1, 12 (t, 3H), 3.13 (s, 4H), 3.80 (s, 2H), 4.09-4.12 (q , 2H), 7.23-7.30 (m, 4H) LRMS (electrospray): m / z [MhT] 274; [MNa +] 296 Microanalysis: Experimental: C, 46.36; H, 5.44; N, 4.41. Ci2Hi6CIN02S. HCI requires C, 46.46; H, 5.52; N, 4.51. Example 13 [2- (4-Chloro-phenoxy) -propylamino] -acetic acid fer-butyl ester A mixture of 2- (4-chloro-phenoxy) -propionaldehfdo1 (0.07 g, 0.38 mmol), fer-butylglycinester (0.054 ml, 0.40 mmol) and triethylamine (0.10 ml, 0.76 mmol) ) in dry dichloromethane (4 mL) was stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (0.12 g, 0.57 mmol) was added in portions and the reaction mixture was stirred at room temperature for 48 hours. The reaction was quenched with saturated sodium hydrogen carbonate (15 mL) and stirred at room temperature for 15 min. The aqueous solution was extracted with dichloromethane (3 x 10 mL), dried over magnesium sulfate, filtered and the solvent was removed by evaporation under reduced pressure. The residue was dissolved in minimal dichloromethane and purified by flash chromatography on silica gel, eluting with a solvent gradient of heptane: ethyl acetate (1: 1) to give the title compound (0.036 g, 25%) as a colorless oil. 1 H NM (400 MHz, CD 3 OD): d = 1.24 (d, 3 H), 1.46 (s, 9 H), 2.74 5 (m, 1 H), 2.86 (m, H), 3 , 30 (s, 2H), 4.50 (m, 1H), 6.91 (d, 2H), 7.21 (d, 2H). LRMS (APCI): m / z [M + H] + 300. 1. Manetti, Dina; Romaneli, María Novella; Bartolini, Alessandro; Dei, Silivia; Gelardini, Carla; Gualtieri, Fulvio; Matucci, Rosanna; Scapecchi, Serena; Teodori, Elisabetta; Arch. Pharm (Weinheim, Germany); 1996, 10 329 (2), 105-11. Example 14 [2- (4-Chloro-phenoxy) -propylamino] -acetic acid The above compound was synthesized using a method similar to Example 6, (0.032 g, 0.11 mmol) of [2- (4-chloro-phenoxy) -propylaminoj-acetic acid fer-t-butylester (Example 13) to produce the compound of the title (0.026 g, 89%) as a white solid. 1 H-NMR (400 MHz, CD 3 OD): d = 1.32 (d, 3 H), 3.36 (m, 2 H), 3.96 (s, 2 H), 4.80 (m, 1 H), 7 , 01 (d, 2H), 7.31 (d, 2H). LRMS (Electrospray): m / z [M + H] + 244. icroanálisis: Experimental: C, 46,96; H, 5.44; N, 4.94. CnH14N03CI.HCI requires C, 47, 16; H, 5.40; N, 5.00%. Example 15 [2- (4-Methylsufanyl-phenylsulfanyl) -ethylamino] -acetic acid ferc-Butylester To a suspension of 2- (4-methylsulfanyl-phenylsulfanyl) ethylamine hydrochloride salt (0.63 g, 2.69 mmol) in anhydrous tetrahydrofuran (20 ml), triethylamine (0.78 ml, 5.64 mmol) was added at 0 ° C under nitrogen. The mixture was stirred for 30 min. To this was added dropwise a solution of urea-butyl bromoacetate (0.42 mL, 2.82 mmol) in anhydrous tetrahydrofuran (10 mL). The mixture was warmed to room temperature and stirred for 18 hours. The solvent was removed under reduced pressure and the residue was partitioned between water (50 ml) and diethyl ether (30 ml). The aqueous phase was extracted with diethyl ether (2 x 30 mL), the combined organics were dried over magnesium sulfate, filtered and the solvent was removed under reduced pressure. The residue was purified by flash chromatography on silica gel, eluting with a solvent gradient of heptane: ethyl acetate (1: 1) to give the title compound (0.25 g, 29%) as a colorless oil. 1 H-NMR (400 MHz, CD 3 OD): d = 1.44 (s, 9 H), 2.45 (S, 3 H), 2.75 (t, 2 H), 3.01 (t, 2 H), 3, 20 (brs, 2H), 7.20 (d, 2H), 7.33 (d, 2H). LRMS (Electrospray): m / z [M + H] + 314.
Microanalysis: Experimental: C, 57.28; H, 7.38; N, 4.41. C15H23NO2S2 requires C, 57.47; H, 7.39; N, 4.47%. Example 16 [2- (4-Methylsufan-1-phenylsulfanyl) -ethylamino] -acetic acid The above compound was synthesized using a method similar to that of Example 6, (0.20 g, 0.64 mmol) of [2- (4-methylsulfanyl-phenylsulfanyl) -ethylamino] -acetic acid-tert-butylester (Example 15) , which was hydrolyzed to yield the title compound (0.17 g, 91%) as a white solid. 1 H-NMR (400 MHz, CD 3 OD): d = 2.47 (s, 3 H), 3.21 (m, 4 H), 3.92 (s, 2 H), 7.25 (d, 2 H), 7, 41 (d, 2H). LRMS (Electrospray): m / z [M + H] + 258. Microanalysis: Experimental: C, 44.92; H, 5.50; N, 4.67. C 11 H 15 NO 2 S 2 HCl requires C, 44.96; H, 5.49; N, 4.77%. Example 17 Acid (4-phenyl-butylamino) -acetic acid A mixture of (4-phenylbutyl-amino) -acetic acid methyl ester (1.38 g, 6.25 mmol) in aqueous HCl 6 (70 mL) was stirred and heated to reflux at 120 ° C for 18 hours. The mixture was cooled to room temperature and the solid was filtered and dried by evaporation under reduced pressure to yield the title compound (1.26 g, 83%) as a white solid. H-NMR (400 Hz, CD3OD): d = 1.71 (m, 4H), 2.68 (m, 2H), 3.05 (m, 2H), 3.88 (m, 2H), 7, 21 (m, 2H), 7.26 (m, 2H). LRMS (APCI): m / z [+ H] + 208. icroanáliis: Experimental: C, 58.99; H, 7.41; N, 5.76. C12HnN02.HCI requires C, 59.14; H, 7.44; N, 5.75%. 2. Braun; Bayer; CHBEAM; Chem.Ber .; 60; 1927; 1259. Example 18 [2- (3-Chloro-phenoxy) -butylamino] -acetic acid Ferric acid butyl ester. { tert-butoxycarbonyl- [2- (3-chloro-phenoxy) -butyl] -amino} Acetic acid (140 mg, 0.33 mmol) was stirred in trifluoroacetic acid (3 mL) and dichloromethane (3 mL) at room temperature for 18 hours. The solvent was removed by evaporation under reduced pressure. The residue was absorbed in 1 M hydrogen chloride (3 mL) and loaded onto Dowex® 50 WX8-200 resin. The resin was eluted with water: ammonia (95: 5) to yield the product as a zwitterion which was stirred in hydrogen chloride in dichloromethane for 1 hour to yield the title compound as a white solid (33 mg, 38%). 1H-NMR (400MHz, CD3OD) d = 0.99 (t, 3H), 1.79 (m 2H), 3.55 (s, 2H), 4.80 (m, 2H), 6.9 (m , 2H), 7.1 (s, 1 H), 7.3 (t, 3H). LRMS (APCI): m / z [M + H] + 258. Example 19 (4-Phenyl-butylamino) -acetic acid methyl ester To a mixture of 4-phenylbutylamine (2.12 ml, 13.4 mmol) and triethylamine (1.84 ml, 13.4 mmol) in anhydrous tetrahydrofuran (30 ml), methyl bromoacetate (1 ml) was added dropwise. , 33 mL, 14.07 mmol) in anhydrous tetrahydrofuran (70 mL) at 0 ° C. The reaction mixture was warmed to room temperature and stirred for 18 hours. The solvent was removed by evaporation under reduced pressure. The residue was diluted with water (50 ml), extracted with diethyl ether (3 x 50 ml), dried over magnesium sulfate, filtered, and the solvent was removed by evaporation under reduced pressure. The residue was dissolved in the minimum amount of dichloromethane and purified by flash chromatography on silica gel, eluting with a solvent gradient of heptane: ethyl acetate (1: 5) to yield the title compound (1.58 g, 55%) as a colorless oil. 1 H-NMR (400MHz, CDCl 3): d = 1.55 (m, 2H), 1.65 (m, 2H), 2.63 (m, 4H), 3.41 (s, 2H), 3.73. (s, 3H), 7.16 (m, 3H), 7.27 (m, 2H). LRMS (APCI): m / z [M + H] + 222.
Micro-analysis: Experimental C, 70.46; H, 8.66; N, 6.33. Ci3HigN02. Requires C, 70.56; H, 8.65; N, 6.33%. PREPARATION 1 Ferric-butyl acetate (2-oxo-1,3-oxazolidin-3-lo) Sodium hydride (60% dispersion in mineral oil, 10.1 g, 0.252 mol) in portions to a stirred solution of 2-oxazolidinone (209, 0.23 mol) in dry tetrahydrofuran (250 ml) at 0 ° C under nitrogen. After stirring for 30 minutes, tert-butyl bromoacetate (50.8 ml, 0.344 mol) was added slowly and the reaction mixture was allowed to warm to room temperature and stirred overnight. Then water was slowly added, followed by ethyl acetate (250 ml). The aqueous phase was extracted and washed with ethyl acetate (50 ml). The combined organic phases were washed with brine (200 ml), dried over magnesium sulfate and concentrated in vacuo. The title compound was crystallized on standing as a white solid (45g, 97%). H-NMR (400 MHz, CDCl 3): d = 1.46 (s, 9H), 3.68 (t, 2H), 3.91 (s, 2H), 4.36 (t, 2H). PREPARATION 2 Acetate rerc-butyl [. { 2 - [(4-Bromophenyl) sulfanyl] ethyl} (urea-butoxycarbonyl) amino] To a stirred solution of the compound of Example 1 (16 g, 46 mmol), in dichloromethane at 0 ° C under nitrogen, was added dropwise a solution of di-fer-butyldicarbonate (11.1 g, 50.9 mmol ) in dichloromethane (50 ml). After 15 hours, the reaction mixture was diluted with dichloromethane (150 ml) and washed successively with sodium hydroxide 1 (200 ml), ammonium chloride (saturated solution, 200 ml), 1 M sodium hydroxide (200 ml). ), brine (300 ml) and dried over magnesium sulfate. The solvent evaporated, producing a light brown light oil that crystallized at rest (18.2 g, 89%). H-NMR (400MHz, CDCl 3): d = 1.44 (d, 9H), 1.47 (d, 9H), 3.07 (t, 1 H), 3, 13 (t, 1 H), 3.40 (t, 1 H), 3.45 (t, 1 H), 3.81 (d, 2 H), 7.24 (d, 2 H) ), 7.39 (d, 2H). MS (Electrospray): [MNa +] 468, [2MNa +] 915. PREPARATION 3 Ferric-butyl acetate (ferc-butoxycarbonyl). { 2 - [(4-cyanophenyl) sulfanyl] ethyl} Not me) The compound of Preparation 2 (3 g, 6.7 mmol), zinc cyanide (787 mg, 6.7 mmol) and tetrakis (triphenylphosphine) palladium (389 mg, 0.34 mmol) in dimethylformamide (50 ml) were mixed. ) dry degassed and heated to 110 ° C for 3 hours. The reaction mixture was then concentrated in vacuo to a thick syrup and water (30 ml) was added under vigorous stirring. The viscous oil was solidified and after filtration, washing with water (3 x 50 mL) and drying under vacuum afforded 2.6 g (99%) of light brown solid. 1 H-NMR (400MHz, CDCl 3): d = 1.45 (d, 9H), 1, 48 (d, 9H), 3.21 (m, 2H), 3.49 (m, 2H), 3.85 (m, 2H), 7.35 (d, 1 H), 7.40 (d, 1 H), 7.53 (d, 2H). MS (Electrospray): m / z [MNa +] 415 [2MNa +] 807 [M-] 391. PREPARATION 4 Recrec-butyl acetate [(2- {[[4- (amnomethyl) phenyl] sulfanyl}. ethyl) (ferc-butoxycarbonyl) amino] To a vigorously stirred suspension of the compound of Preparation 3 (300 mg, 0.76 mmol) and cobalt chloride (364 mg, 1.53 mmol) in methanol (10 mL) at -10 ° C under nitrogen, was added sodium borohydride (291 mg, 7.6 mmol) in portions. The black reaction mixture was allowed to warm to room temperature, stirred for 2.5 hours, cooled suddenly with 5% aqueous HCl (50 ml) followed by water (15 ml) and 35% aqueous ammonia (40 ml), and extracted with ethyl acetate (3 x 300 ml). The title compound was isolated after chromatography on silica (eluent: gradient of dichloromethane to dichloromethane / methanol 9/1) as a white solid (40 mg, 13%). 1 H-NMR (400MHz, CDCl 3): d = 1, 42 (d, 9H), 1, 44 (d, 9H), 3.08 (m, 2H), 3.44 (m, 2H), 3.79 (d, 2H), 3.86 (s, 2H), 7.26 (d, 2H), 7.31 (d, 2H). MS (Electrospray): m / z [MH +] 397 [MNa +] 419 [2MH +] 793. TLC: rf = 0.1 in dichloromethane / methanol (9/1). PREPARATION 5 2,4-Dichloro-1- (2-chloroethoxy) benzene To 1 g (6.1 mmol) of 2,4-dichlorophenol in 10 ml of anhydrous dimethylformamide under a nitrogen atmosphere was added 270 mg (6.75 mmol) of 60% sodium hydride / oil dispersion. . After stirring for 5 minutes, this solution was added dropwise to 10 ml of 1-bromo-2-chloroethane dissolved in 20 ml of anhydrous dimethylformamide and stirred for 24 hours at room temperature. The solvent was removed under reduced pressure and the residue was dissolved in ethyl acetate (100 ml) and washed with water (1 x 50 ml). The organic layer was dried (MgSO 4), filtered and evaporated under reduced pressure. The resulting oil was purified by chromatography column over silica gel, eluting with pentane to give the title compound (1 g, 73%) as a colorless oil. 1 H-NMR (400MHz, CDCl 3) d = 3.80-3.85 (t, 2H), 4.22-4.28 (t, 2H), 7.84-7.88 (d, 1H), 7.16-7.20 (d, 1 H), 7.38 (S, 1 H). PREPARATION 6 Di (ferc-butyl) 2- (2,4-dichlorophenoxy) ethylamidodicabonate To 1 g (4.4 mmol) of 2,4-dichloro-1- (2-chloroethoxy) benzene in 10 ml of anhydrous dimethylformamide was added 1.06 g (4.4 mmol) of di ( tert-butyl) midodicarbonate and heated at 90 ° C for 16 hours. The solvent was removed under reduced pressure and the residue was dissolved in ethyl acetate (100 ml) and washed with water (2 x 50 ml). The organic layer was dried (MgSO4), filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with a solvent gradient of pentane to 9: 1 pentane: diethylether to yield the title compound (700 mg) as a colorless oil. 1 H-NMR (400MHz, CDCl 3) d = 1, 49-1, 51 (S, 18H), 4.02-4.05 (t, 2H), 4.15-4.18 (t, 2H), 6 , 84 (d, 1 H), 7.15 (d, 1 H), 7.34 (S, 1 H).
PREPARATION 7 2- (2,4-Dichlorophenoxy) ethanamine 700 mg (1.7 mmol) of di (fer-butyl) 2- (2,4-dichlorophenoxy) ethylimidodicarbonate were dissolved in 15 ml of anhydrous hydrogen chloride 4 in dioxane solution and stirred for 2 hours at room temperature. The solvent was removed under reduced pressure and the residue was purified by trituration with ethyl acetate, which after filtration afforded the title compound (350 mg, 100%) as a white solid. 1H-NMR (400MHz, D20) d = 3.33-3.38 (t, 2H), 4.18-4.25 (t, 2H), 6.95-7.00 (d, 1H), 7.18-7.23 (d, 1 H), 7.40 (s, 1 H) LRMS (thermospray): m / z [MH +] 206; [MNa +] 238. PREPARATION 8 7-lsoquinolinatiol Triisopropylsilanethiol (6.49 g, 34.08 mmol) was added dropwise to a suspension of sodium hydride (1.36 g, 3.4 mmol, 60% dispersion in oil) in THF (100 mL), and the The mixture was stirred at room temperature for 20 minutes. Palladium (0) tetrakis (triphenylphosphine) (3.0 g, 2.5 mmol) and then a solution of isoquinoline-7-trifluoromethanesulfonate (9.0 g, 32.5 g) were added. mmol, Beilstein reg. No. 5439845) in THF (80 ml), and the reaction was heated to reflux for 18 hours. After cooling to room temperature, the mixture was partitioned between ethyl acetate (150 ml) and water (75 ml). The phases were separated and the aqueous washed with ethyl acetate (2 x 50 mL). The combined organic extracts were backwashed with saturated aqueous sodium chloride solution (50 ml), dried over magnesium sulfate, filtered and the filtrate was evaporated under reduced pressure. The crude material was purified by chromatography on silica (350 g), eluting with a solvent gradient of dichloromethane (100: 0 by volume) gradually changing to dichloromethane: methanol (100: 10 by volume) to yield deprotected thiol. The thiol was dissolved in a minimum of hot ethanol and the gravity filtered to remove a small amount of insoluble material. The filtrate was cooled on ice to obtain the title compound (1.16 g, 21%) as a creamy crystalline solid. 1 H-NR (400 Hz, CDCl 3): d = 7.63 (d, 1H), 7.76-7.88 (m, 2H), 8.12 (s, 1H), 8.52 (d, 1 H), 9.18 (s, 1 H). LR S (electrospray): [M-1] 160 PREPARATION 9 2- (4-Methylsulfanyl-phenylsulfanyl) ethylamine hydrochloride salt A mixture of 4- (methylthio) thiophenol (1 g, 6.34 mmol), sodium hydrogen carbonate (0.54 g, 6.40 mmol) and sodium hydrobromide salt were stirred. 2-Bromo-ethylamine (1.48 g, 7.13 mmol) in absolute ethanol (20 mL), refluxed (90 ° C) for 6 hours. The reaction mixture was cooled to room temperature and the solvent was removed under reduced pressure. The solid was partitioned between 1 M hydrochloric acid (50 ml) and diethyl ether (50 ml). The aqueous product was washed with diethyl ether (2 x 50 mL), evaporated under reduced pressure, washed with ethyl acetate (3 x 10 mL) and the solid was dried to yield the title compound (0.66 g, 44%). %) as a white solid. 1H-NMR (400 Hz, D20): d = 2.35 (s, 3H), 3.02 (m, 2H), 3.07 (m, 2H), 7.19 (d, 2H), 7, 31 (d, 2H). LR S (APCI): m / z [M + H] + 200. PREPARATION 10 tert-Butylester (2-hydroxybutylamino) -acetic acid To a solution of 1-amino-2-butanol (4.69 g, 5.26 mmol) in anhydrous diethyl ether (100 ml), triethylamine (1.88 ml, 13.49 mmol) was added, followed by the addition drop by drop of 1-bromo - / - butyl acetate (4.23 ml, 13.49 mmol) in diethyl ether (25 ml). The mixture was stirred at 0 ° C for 3 hours, then warmed to room temperature and stirred for 18 hours. The mixture was washed with water (50 ml) and extracted with diethyl ether (2 x 50 ml). The organic layer was washed with brine (30 ml), dried over magnesium sulfate, filtered and the solvent was removed after evaporation under reduced pressure to yield the intermediate compound (3.07 g, 89%) as a colorless oil. 1H-NMR (400MHz, CD3OD): d = 0.94 (t, 3H), 1.46 (2 xs, 11 H), 2.48 (dd, 1H), 2.62 (dd, 1 H), 3.29 (d, 2H), 3.56 (m, 1 H). LRMS (APCI): m / z [M + H] + 204. PREPARATION 11 tert-Butylester [ferc-butoxycarbonyl- (2-hldroxybutyl) -amino] -acetic acid To a stirred solution of (2-hydroxybutylamino) -acetic acid (2-hydroxybutylamino) -acryclic acid ester (2.74 g, 13.48 mmol) in dioxane (100 mL), was added di-ert-butyldicarbonate (2.94 g, , 48 mol), with subsequent addition of sodium acetate (0.81 g, 13.48 mmol) in water (15 ml) and stirred at room temperature for 4 hours. The solvent was removed by evaporation under reduced pressure. The residue was diluted with water (30 ml), extracted with ethyl acetate (3 x 50 ml), dried over magnesium sulfate and the solvent was removed by evaporation under reduced pressure to yield the title compound (2.24). g, 55%) as a colorless oil. 1H-NMR (400MHz, CD3OD): d = 0.94 (t, 3H), 1.40 (m, 2H), 1.44 (3 xs, 18H), 3.03 (m, 1H), 3, 43 (m, 1 H), 3.62 (m, 1 H), 3.88 (d, 1 H), 3.94 (d, 1 H).
LRMS (APCI): m / z [M + H] + 304. icroanalysis: Experimental C, 59.06; H, 9.70; N, 4.51. C15H29N05 Requires C, 59.38; H, 9.63; N, 4.62%. PREPARATION 12 To a stirred solution of tert-butyl ester [tere-butoxycarbonyl- (2-hydroxy-butyl) -amino] -acetic acid (300 mg, 0.99 mmol) in tetrahydrofuran (10 ml) was added triphenylphosphine (273 mg, 1. 04 mmol) and 3-chlorophenol (133 mg, 1.04 mmol). It was cooled to 0 ° C and diisopropylazodicarboxylate (239 mg, 1.04 mmol) in tetrahydrofuran (5 ml) was added dropwise over 1 hour. The reaction mixture was warmed to room temperature and stirred for 18 hours. The solvent was removed under reduced pressure and the residue was taken up in heptane: ethyl acetate (1: 1) and stirred for 1 hour. The precipitate was filtered and the filtrate was concentrated, taken up in ethyl acetate and washed with 2N HCl (3 x 20 mL) and dried over magnesium sulfate. The solvent was removed by evaporation under reduced pressure and the residue was purified by flashmaster® column chromatography on silica gel, eluting with heptane: ethyl acetate (15: 1) to yield the title compound (250 mg, 60%). as a clear oil. 1H-NMR (400MHz, CD3OD): d = 0.98 (m, 3H), 1.45 (d, 18H), 1.65 (q, 2H), 3.32 (m, 1 H), 3, 65 (d, 1H), 3.85 (6, 2H), 4.48 (m, 1 H), 6.85 (m, 1 H), 6.90 (m, 2H), 7.2 (m , 1 HOUR). LRMS (ESI) m / z [M-H] + 412. Micro-analysis: Experimental C, 60.68; H, 7.84; N, 3.44. C 21 H 32 CINO 5 requires C, 60.93; H, 7.79; N, 3.43%. Examples of pharmaceutical compositions In the following Examples, the active compound can be any compound of the formula (I) and / or one of its pharmaceutically acceptable salts, solvates or physiologically functional derivatives. (i) Compositions in tablets The following compositions A and B can be prepared by wet granulation of ingredients (a) to (c) and (a) to (d) with a solution of povidone, followed by the addition of magnesium stearate and compression.
Composition A mq / tablet mg / tablet (a) Active ingredient 250 250 (b) Lactose B.P. 210 26 (c) Sodium starch glycolate 20 12 (d) Povidone B.P. 15 9 (e) Magnesium stearate 5 3 500 300 Composition B mq / comorimido mq / comDrimido (a) Active ingredient 250 250 (b) Laclosa 150 150 (c) Avicel PH 101 60 26 (d) Sodium starch glycolate 20 12 (e) Povidone B.P. 15 9 (f) Magnesium stearate 5 3 500 300 Composition C mq / tablet Active ingredient 100 Lactose B.P. 200 Starch 50 Povidone 5 Magnesium stearate 4 359 The following compositions D and E can be prepared by direct compression of the mixed ingredients. The lactose used in formulation E is of the direct compression type. Composition D mq / tablet Active ingredient 250 Magnesium stearate 4 Pre-gelatinised starch NF15 146 400 Composition E mg / tablet Active ingredient 250 Magnesium stearate 5 Lactose 145 Avicel 100 500 Composition F (Controlled release composition) mg / tablet (a) Active lngrediente (b) Hydroxypropylmethylcellulose (Methocel K4M (c) Lactose B.P. (d) Povidone B.P.C. (e) Magnesium Stearate The composition can be prepared by wet granulation of the ingredients (a) to (c) with a solution of povidone, followed by the addition of magnesium stearate and compression. Composition G (Enteric coated tablet) The enteric coated tablets of Composition C can be prepared by coating the tablets with 25 mg / tablet of an enteric polymer such as cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropylmethylcellulose phthalate, or anionic polymers of methacrylic acid and methacrylic methylester (Eudragit L). Except for Eudragit L, these polymers should include 10% (by weight of the amount of polymer used) of a plasticizer to prevent membrane breakage during application or storage. Suitable plasticizers include diethyl phthalate, tributyl citrate and triacetin. Composition H (Enteric coated controlled release tablet) Enteric coated tablets of Composition F can be prepared by coating the tablets with 50 mg / tablet of an enteric polymer cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate or ammonium polymers of methacrylic acid and methacrylic methylester (Eudgragit L). Except for Eudgragit L, these polymers should also include 10% (by weight of the amount of polymer used) of a plasticizer to prevent rupture of the membrane during application or storage. Suitable plasticizers include diethyl phthalate, tributyl citrate and triacetin. (ii) Capsule Compositions Composition A Capsules can be prepared by mixing the ingredients of Composition D above and filling two-part hard gelatin capsules with the resulting mixture. Composition B (infra) can be prepared in a similar manner.
Composition B (a) Active Ingredient (b) Lactose B.P. (c) Sodium starch glycolate (d) Magnesium stearate 420 Composition C mq / capsule (a) active ingredient 250 (b) Macrogol 4000 BP 350 600 The capsules can be prepared by mixing Macrogol 4000 BP, dispersing the active ingredient in the mixture and filling it with two-part hard gelatin capsules. Composition D mq / capsule Active ingredient 250 Lecithin 100 Peanut oil 100 450 Capsules can be prepared by dispersing the active ingredient in the lecithin and peanut oil and filling the soft elastic gelatin capsules with the dispersion.
Composition E (Controlled release capsule) (a) Active ingredient 250 (b) Microcrystalline cellulose 125 (c) Lactose B.P. 125 (d) Ethylcellulose 13 513 The controlled release capsule formulation can be prepared by extruding the mixed ingredients (a) to (c) using an extruder, then forming spheres and drying the extrudate. Then the dried mini-spheres are coated with a release control membrane (d) and filled into two-part hard gelatin capsules. Composition F (Enteric capsule) mq / capsule (a) active ingredient 250 (b) Microcrystalline cellulose 125 (c) Lactose B.P. 125 (d) Cellulose acetate phthalate 50 (e) Diethyl phthalate 5 555 The enteric capsule composition can be prepared by extruding the mixed ingredients (a) to (c), using an extruder, then forming spheres and drying the extrudate. The dried microspheres are coated with an enteric membrane (d) containing a plasticizer (e) and filled into two-part hard gelatin capsules.
Composition G (Enteric coated controlled release capsule) The enteric capsules of composition E can be prepared by coating the controlled release microspheres with 50 mg / capsule of an enteric polymer such as cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropylmethylcellulose phthalate or anionic polymers of methacrylic acid and methacrylic methylester (Eudragit L). Except for Eudragit L, these polymers should include 10% (by weight of the amount of polymer used) or a plasticizer to prevent rupture of the membrane during application or storage. Suitable plasticizers include diethyl phthalate, tributyl citrate and triacetin. (iii) Composition in intravenous injection Active Ingredient 0.200g Sterile, pyrogen-free phosphate buffer (pH 9.0) a The active ingredient is dissolved in the majority of phosphate buffer at 35-0T, then formed to volume and filtered through a sterile micropore filter in sterile 10 ml glass vials (Type 1) that are sealed with closures and sterile fillings. (iv) Composition in intramuscular injection Active ingredient 0.20 g Benzyl alcohol 0.10 g Glyofurol 75 1.45 g Water for injection e s. up to 3.00 mi The active ingredient dissolves in glycofurol. The benzyl alcohol is then added and dissolved, and water is added to 3 ml. The mixture is then filtered through a sterile micropore filter and sealed in 3 ml sterile glass vials (Type 1). (v) Syrup composition Active ingredient 0.25 g Sorbitol solution 1.50 g Glycerol 1.00 g Sodium benzoate 0.005 g Flavor 0.0125 ml Purified water is. Up to 5.0 mi The sodium benzoate is dissolved in a portion of purified water and the sorbitol solution is added. The active ingredient is added and dissolved. The resulting solution is mixed with the glycerol and then the required volume is formed with the purified water. (i) Composition in suppository mq / surx > sitorio Active ingredient 250 Hard fat, BP (Witepsol H15-Dynamit NoBel) 770 2020 One fifth of the Witepsol H15 is melted in a steam jacketed vessel at a maximum of 45 ° C. The active ingredient is sieved through a 200 Im sieve and added to the molten base by mixing, using a Silverson equipped with a cutter head, until a uniform dispersion is achieved. Maintaining the mixture at 45 ° C, the remaining Witepsol H15 is added to the suspension which is agitated until a homogeneous mixture is ensured. The total suspension is then passed through a 250 Im stainless steel sieve and, with continuous agitation, allowed to cool to 40 ° C. At a temperature of 38-40 ° C, 2.02 g of aliquots of the mixture are poured into suitable plastic molds and the suppositories are allowed to cool to room temperature. (vii) Composition in pessaries mg / pessary Active ingredient (63 Im) 250 Dextrose anhydrous 380 Potato starch 363 Magnesium stearate 7 1000 The aforementioned ingredients are mixed directly and pessaries are prepared by compression of the resulting mixture. (vüi) Transdermal composition Active ingredient 200 mg Alcohol USP 0,1 mi Hydroxyethylcellulose The active ingredient and alcohol USP are gelled with hydroxyethylcellulose and packed in a transdermal device with a surface area of 10cm2. Biological Data The compounds of the invention were tested in the described radioligand binding assay and found to possess affinities towards binding in the following manner; Activity Example (nM) 9 1665 8 987 12 5406 6 198 10 507 11 71 7 59

Claims (1)

  1. CLAIMS 1. The use of a compound of the formula (I) or a pharmaceutically acceptable salt or solvate thereof as a medicament; Formula (I) wherein R 1 is hydroxycarbonyl, a biosterol carboxylic acid or one of its prodrugs; R3, R3a, R2 and R2 are independently selected from H, C1-C6 alkyl and C1-C6 alkoxy C1-C6 alkyl; and Z is; (i) a 5-membered heteroaryl or heterocycloalkyl linked to C, substituted with C 1 -C 6 alkyl or fused with C 3 -C 8 cycloalkyl, monocyclic heteroaryl, phenyl or 4-8 membered heterocycloalkyl, wherein the fused ring is optionally substituted with one or two substituents selected from the group consisting of halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 perfluoroalkyl, C 1 -C 6 perfluoroalkoxy, cyano, C 1 -C 6 amino alkyl, C 1 -C 6 alkyl, C 3 cycloalkyl C8, monocyclic heteroaryl, phenyl and 4-8 membered heterocycloalkyl; or (ii) the group; wherein R4 and R4a are independently H, CrC6 alkyl or C-C6 alkoxy CI-CQ alkyl, R5 is Ci-C6 alkyl, C3-C12 cycloalkyl, aryl, heteroaryl or 4-12 membered heterocycloalkyl and R5 is optionally substituted with one or two substituents selected from the group consisting of halogen, C 1 -C 6 alkyl, CrC 6 alkoxy, CrCe perfluoroalkyl, Ci-C 6 perfluoroalkoxy, cyano, C 1 -C 6 alkyl, amino, CrCB amino dialkyl, Ci-C 6 aminoalkyl C 1 -C 6 alkyl aminoC alkyl CrC 6 , C 1 -C 6 dialkyl aminoalkyl C Ce, C 1 -C 6 alkyl thio, C 3 -C 8 cycloalkyl, monocyclic heteroaryl, phenyl and 4-8 membered heterocycloalkyl; I am good; (i) Y is S, O, CH2 or NH and X is a direct bond or C1-C2 alkyl, optionally substituted with C1-C6 alkyl, C1-C6 dialkyl or 1-4 fluorine atoms; or (ii) X is S, O, CH2 or NH and Y is C1-C2 alkyl, optionally substituted with CrCe alkyl, C1-C6 dialkyl or 1-4 fluorine atoms. 2. The use of a compound of the formula (I) according to claim 1 or a pharmaceutically acceptable salt or solvate thereof in the manufacture of a medicament for the treatment of a disease selected from epilepsy, syncope, hypokinesia, disorders cranial, neurodegenerative disorders, depression, anxiety, panic, pain, irritable bowel syndrome, sleep disorders, osteoarthritis, rheumatoid arthritis, neuropathological disorders, visceral pain, functional bowel disorders, Inflammatory bowel diseases, pain associated with dysmenorrhea, pelvic pain, cystitis and pancreatitis. 3. Use of a compound according to claim 1 or claim 2, wherein Y is S, CH2 or O and X is a direct bond or C1-C2 alkyl. 4. Use of a compound according to claim 1 or claim 2, wherein X is S, CH2 or O and Y is CVC2 alkyl. 5. Use of a compound according to any one of claims 1-4, wherein R2, R2a, R3, R3a, R4 and R4a are H or Ci-C6 alkyl. 6. - Use of a compound according to any one of claims 1-5, wherein R5 is aryl or heteroaryl and is optionally substituted with one or two substituents selected from halogen, C1-C6 alkyl, Ci-C6 alkoxy, perfluoroalkyl CrC6, perfluoroalkoxy C1-C6, alkyl CrC6 thio and aminoalkyl C1-C6. 7. Use of a compound of the formula (II) or a pharmaceutically acceptable salt or solvate thereof as a medicament; Formula (II) wherein R8 and R9 are independently H, halogen, d-Ce alkyl, C1-C6 perfluoroalkyl, C1-C6 perfluoroalkoxy, C1-C6 alkyl thio or aminoalkyl Ci-Ce; and R10 is H or Ci-Ce alkyl. 8. - Use of a compound of the formula (III) or a pharmaceutically acceptable salt or solvate thereof as a medicament; f¾rmui »(III) that R11 is H or C1-C6 alkyl. Use according to claim 1 or claim 2, wherein the compound is selected from the group consisting of; urea-butyl acetate (. {2 - [(4-bromophenyl) sulfanyl) ethyl} amino); urea-butyl acetate (. {2 - [(4-chlorophenyl) sulfanyl] ethyl} amino); urea-butyl acetate. { [2- (2,4-dichlorophenoxy) ethyl] amino}; urea-butyl acetate (. {2 - [(4-chlorobenzyl) sulfanyl] et.l.} amino); urea-butyl acetate. { [2- (7-isoquinolinylsulfanyl) ethyl] amino}; ( {2 - [(4-chlorophenyl) sulfanyl] ethyl} amino) acetic acid; ( {2 - [(4-Bromophenyl) sulfanyl] ethyl] amino) acetic acid; [(2- {[[4- (amnomethyl) phenyl] sulfanyl] ethyl] amino] acetic acid; acid { [2- (2,4-dichlorophenoxy) ethyl] amino} acetic; ( {2 - [(4-Chlorobenzyl) sulfanyl] ethyl} amino) acetic acid; acid { [2- (7-isoquinolinylsulfanyl) ethyl] amino} acetic; ethyl acetate (. {2 - [(4-chlorophenyl) sulfanyl] ethyl} amino); [2- (4-chloro-phenoxy) -propylamino] -acetic acid ferc-butylester; [2- (4-chloro-phenoxy) -propylamino] -acetic acid hydrochloride salt; [2- (4-Methylsufanyl-phenylsufanyl) -ethylamino] -acetic acid re-tert-butylester; [2- (4-Methylsufanyl-phenylsufanyl) -ethylamino] -acetic acid hydrochloride salt; (4-phenyl-butylamino) -acetic acid methyl ester; 4-phenylbutylamino acetic acid hydrochloride salt; and [2- (3-chloro-phenoxy) -butylamino] -acetic acid; dihydrochloride. 10. - A pharmaceutical composition comprising a compound of the formula (I) according to any one of claims 1-9 and one or more pharmaceutically acceptable excipients and vehicles. 11. - A method to treat a disease selected from epilepsy, syncopes, hypokinesia, cranial disorders, neurodegenerative disorders, depression, anxiety, panic, pain, irritable bowel syndrome, sleep disorders, osteoarthritis, rheumatoid arthritis, neuropathological disorders, visceral pain , functional intestinal disorders, inflammatory bowel diseases, pain associated with dysmenorrhea, pelvic pain, cystitis and pancreatitis in a mammal, comprising administering to said mammal a compound of the formula (I), as claimed in any one of the claims 1-9. 12. - A process for the preparation of a compound of the formula (I); wherein R1, R2, R2a, R3, R3a and Z are as defined in claim 1, comprising: (A) reacting a compound of the formula (IV) with a compound of the formula (V) , or a compound of the formula (VI) with a compound of the formula (VII); where L is a leaving group; or (B) deprotection of a compound of the formula (VIII); (VHI) in which PG is a suitable protective group; or (C) wherein X is a direct bond or C C2 alkyl, ring opening of a compound of the formula (X) or (XIII) by the addition of a compound of the formula (XI); 5 - X - YH (XI) wherein R4, R4a, R5, X and Y are as defined in claim 1. SUMMARY The compounds of the formula (I) are substituted glycine derivatives useful in the treatment of epilepsy, syncope, hypokinesia, cranial disorders, neurodegenerative disorders, depression, anxiety, panic, pain, arthritis, neuropathological disorders, sleep disorders, visceral pain and gastrointestinal disorders. Procedures for the preparation of the final and intermediate products useful in the process are included. Also included are pharmaceutical compositions containing one or more of the compounds. Formula (i) wherein R 1 is hydroxycarbonyl, a biosterol carboxylic acid or one of its prodrugs; R3, R3a, R2 and R2a are independently selected from H, d-C6 alkyl and Ci-C6 alkoxy CrC6 alkyl; Z is; (i) a 5-membered C-linked heteroaryl or heterocyclic alkyl substituted with Ct-Ce alkyl or fused with C3-C8 cycloalkyl, monocyclic heteroaryl, phenyl or 4-8 membered heterocyclyalkyl, wherein the fused ring is optionally substituted with or one or two substituents selected from the group consisting of halogen, CrC6 alkyl, Ci-C6 alkoxy, Ci-C6 perfluoroalkyl, perfluoroalkoxy d-Ce, cyano, Ci-C6 amino alkyl, CI-CB alkyl thio, C3-CE cycloalkyl, monoclonal heteroaryl, phenyl and 4-8 membered heterocycloalkyl; or (ii) the group; wherein R 4 and R a are independently H, C C 6 alkyl, C 6 C alkoxy or C C 6 alkoxy C 1 -C 6 alkyl; R5 is C -Ce alkyl, C3-C12 cycloalkyl, aryl, heteroaryl or 4-12 membered heterocycloalkyl and R5 is optionally substituted with one or two substituents selected from the group consisting of halogen, Ci-Ce alkyl, C1-C6 alkoxy , C1-C6 perfluoroalkyl, C1-C6 perfluoroalkoxy, cyano, C1-C6 amino alkyl, C1-C6 amino dialkyl, Ci-C6 aminoalkyl, C1-C6 alkyl C1-C6 aminoalkyl, dialkyl CrC6 aminoalkyl Ci-Ce, alkyl C ^ Ce thio, C3-CB cycloalkyl, monocyclic heteroaryl, phenyl and 4-8 membered heterocycloalkyl; I am good; (i) Y is S, O, NH or CH2 and X is a direct bond or C1-C2 alkyl optionally substituted with C1-C6 alkyl or C6 dialkyl or 1-4 fluorine atoms; or (i) X is S, O, CH2 or NH and Y is C1-C2 alkyl optionally substituted with Ci-C6 alkyl or dialkyl Ci-Ce or 1-4 fluorine atoms.
MXPA05000979A 2002-08-16 2003-08-04 Substituted glycine derivatives for use as medicaments. MXPA05000979A (en)

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